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!Sandler Asthma Basic REsearch Center!University of California, San Francisco!!Progress Report!Year 14!April 2013!Innate Lymphoid Cells in Asthma!

Figure Legend: Lung slices from mice before and after allergen challenge were imagedusing three-channel multiphoton microscopy. Animals contain a red fluorescent markerintroduced into the interleukin-5 gene, which reveals IL-5-producing innate lymphoidcells organized at airway branchpoints that respond to provocation by activating cytokineexpression. IL-5 is critical for recruiting and sustaining eosinophils, a central cell typeseen in allergic asthma. Image courtesy of Emily Thornton, Steve Van Dyken, JesseNussbaum from the laboratories of Drs. Krummel and Locksley.

TABLE OF CONTENTSMission StatementOverviewSummary of AccomplishmentsExecutive Committee: Members and FunctionsScientific Advisory BoardMitchell Kronenberg, Ph.D.Philippa Marrack, Ph.DChristopher Wilson, M.D.SABRE Center InvestigatorsRichard Locksley, M.D., Ph.D.Christopher Allen, Ph.D.K. Mark Ansel, Ph.D.Limin Liu, Ph.D.Jeoung-Sook Shin, Ph.D.Core FacilitiesMouse Physiology and MorphologyFunctional GenomicsGeneticsCell Sorting and AnalysisMicroscopyAsthma Related Research ProjectsEvolving Microenvironments in Airway InflammationNIAID Asthma and Allergic Diseases Cooperative Research CenterContributions to Relevant Scientific ActivitiesPublications Supported by the Sandler Asthma BasicResearch CenterLooking to the FutureBiographical Sketches

Mission StatementThe Sandler Asthma Basic Research Center (SABRE Center) at UCSF is an investigative unitdedicated to basic discovery in asthma research. The SABRE Center is nucleated by a smallgroup of five basic scientists who are supported by advanced technology cores and linked withthe larger scientific community through Center Grants and Program Project Grants focusedaround asthma research. Strong linkage with the Airway Clinical Research Center at UCSF hasenabled increasing focus on human studies. Regular seminars promote additional integration ofthe SABRE Center into the more extended UCSF research community to facilitate collaborationand to increase awareness for needs in fundamental discovery in asthma research. Founded in1999, the SABRE Center is made possible by the generous support of the Sandler Foundation.Summary of Accomplishments over the Past YearThe SABRE Center is evolving into a successful research enterprise within the greater UCSFscientific community. Notable benchmarks achieved this year include: (1) the award of an NIHDirector’s New Innovator Award to Chris Allen, the SABRE Center UCSF Fellow, who wasrecruited to stay at UCSF on the faculty as a member of the Cardiovascular Research Institute,where he will continue his work as a SABRE Center member; (2) the first full year of funding ofthe SABRE Center Program Project grant to study the role of innate lymphoid cells in humanasthma using patients accrued from the Airway Clinical Research Center; (3) the successfulrenewal of the NIH NIAID Asthma and Allergic Diseases Cooperative Research Center tocontinue investigations of cytokine regulation of airway smooth muscle contraction; (4) thesuccessful organization and planning of a Keystone Symposium in January 2013 devoted torecent advanced in Type 2 Immunity and Pathogenic Processes in Asthma in Santa Fe, NewMexico, that drew over 250 scientists together; and (5) continued successes in obtainingextramural funding and publishing high impact manuscripts in competitive journals.Increasingly, these studies have begun to work with and focus on human patients and materialsand the interactions with our clinical colleagues in the Pulmonary Division continue tostrengthen with the establishment of the Airway Clinical Research Center. We look forward toongoing successes in the coming year as we continue with our mission to conquer asthma.2

Overview – 2013Richard M. Locksley, M.D.The SABRE Center consists of the Director, Dr. Locksley, three full-time faculty, Drs. Ansel,Liu and Shin, and one UCSF Fellow, Dr. Allen, who has just completed his five yearappointment and has been recruited to join the faculty. In turn, these investigators now support10 postdoctoral trainees, 9 graduate students in Immunology and Biomedical Sciences, and 3professional staff. Dr. Chapman, the former head of the Pulmonary Division at UCSF, works incontiguous space. His interests focus on lung inflammation and fibrosis, which overlap theinterests of the SABRE Center. The SABRE Center maintains close working relationships withthe Airway Clinical Research Center (ACRC) under the leadership of Dr. John Fahy, who hasbecome a member of the Executive Board. The fruits of this collaborative effort resulted in thefirst NIH Program Project Grant awarded to SABRE investigators beginning in 2012, with amajor focus centered on human patients and tissues as organized through the ACRC. TheSABRE Center has evolved into a self-standing research addition to the UCSF campus with thecapacity to contribute to our understanding of this important human disease. We will review theindividual investigators and their progress, followed by an overview of the constituents of theCenter, a brief discussion of achievements and finally a look at the extramural grants that havebeen obtained to support these activities.InvestigatorsDr. Ansel is working to understand the gene expression pathways that mediate differentiationand regulation of cell fate and function in allergy, particularly asthma. His focus remains onmicroRNAs, transcription factors and epigenetics as critical executioners of these pathways. Hecontinues to push new technologies relevant to his studies, including a method for assessingmicroRNA targets by demonstrating their associations with the miRISC processing complex, ananalysis which could greatly spur the field. He published 4 manuscripts in 2012-13 as seniorauthor and contributed to a fifth; an additional manuscript is under revision at NatureImmunology and describes the role of a specific microRNA, miR-17~92, in follicular T celldifferentiation. He is building increasing excitement over his discoveries in the field asevidenced by recognition of his early achievements through solid publications and enhancedamounts of extramural grant support. He was asked to write a review on RNA regulation of theimmune system for Nature Reviews Immunology and to organize an issue of ImmunologicalReviews on the subject, attesting to his recognition by leaders in the field. Dr. Ansel participatedin several national and international scientific conferences related to his expertise, including talksin Japan and Korea.Based on studies completed with his 3-year Dana Foundation Award, Mark received his firstR01 funded grant from the National Heart, Lung and Blood Institute of the NIH to pursuecollaborations with Dr. Prescott Woodruff in the Airway Clinical Research Center, bringing in$1,796,403 in direct research dollars over a five year period. Dr. Ansel also was a participatingPrincipal Investigator as part of the first Program Project Grant among SABRE Investigatorsfrom the NIH. This grant began funding in July 2012 at a total level of approximately3

$1,575,000 per year over the next 5 years. In recognition of his outstanding accomplishments asa young investigator, Dr. Ansel was awarded a Leukemia & Lymphoma Society Scholar Award,resulting in approximately $525,000 in direct costs from 2012-2017. He has a U19 applicationunder consideration that involves a concerted effort towards understanding microRNAbiogenesis and regulation in immune cells using allergic immunity as a template.Personnel in the Ansel laboratory include two graduate students, with one supported byNational Science Foundation Predoctoral Research Fellowship and one a recipient of an HHMIGraduate Education in Medical Science (GEMS) Training Program Award to pursuetranslational studies in asthma patients in collaboration with Dr. Fahy in the Airway ClinicalResearch Center. The postdoctoral fellow is supported by a Swiss National Fellowship. Dr.Ansel’s first student graduated and is doing a postdoctoral fellowship. He is actively pursuingstudies using materials collected from patients with asthma in the Airway Clinical ResearchCenter. He is collaborating in studies with the Functional Genomics Core, the AnimalPhysiology Core and the Flow Cytometry Core. He collaborates with multiple otherinvestigators in the SABRE Center.In recognition of Dr. Ansel’s success to date, the Department of Microbiology & Immunologyhas submitted his materials for consideration of early advancement to Associate Professor.Dr. Liu is pursuing the mechanisms that control the targeting and turnover of nitric oxide, animportant airway and blood vessel relaxant. Work in his postdoctoral training identified theenzyme GSNOR as an important molecule regulating nitrosylation and nitric oxide turnover intissues, and this molecule has become an important target in asthma, although it will be critical tofirst identify potential toxicities that might be associated with inhibiting this pathway. Duringhis studies at UCSF, Dr. Liu identified an important role for GSNOR in protecting liver cellsfrom genotoxic stress. He went on to identify the mechanism as linked to the nitrosativeinactivation of a DNA alkyltransferase involved in DNA repair. He continues to address the roleof GSNOR in immune pathways related to asthma in a collaborative publication with Dr.Krummel in the Imaging Core and in on-going but incomplete studies addressing cell-specificdeletion of GSNOR in different lung cell populations in order to pinpoint the origin of GSNORamenable to therapeutic intervention in asthma. He is actively attempting to identify the targetsof protein nitrosylation potentially impacted by this pathway. He had two manuscripts related toGSNOR in publication over the past year and two additional manuscripts submitted. He hasbeen working recently with Dr. Steven An to define direct roles for GSNOR in airway smoothmuscle cell contraction and relaxation pathways. Dr. Liu is working collaboratively withindividuals in the Functional Genomics, Genetics and Flow Cytometry Cores. He presented hiswork at both national and international scientific meetings.Dr. Liu is supported by an R01 and P01 on which he participates. These grants, whichcontribute over $475,000 direct costs per year, are from the National Cancer Institute of the NIHand study aspects of oncogenesis mediated by GSNOR deficiency, an important issue that mustbe addressed in order to sustain interest in this enzyme as a viable asthma therapeutic target. Hehas three postdocs in his laboratory. He continues to work to develop sufficient preliminary andpublished information on the role of GSNOR in smooth muscle contraction in order to pursuethis as an asthma-related source of NIH funding. Dr. Liu was promoted to Associate Professor,4

effective July 2012, thus becoming the first SABRE Center recruit to achieve academic tenure atUCSF.Dr. Shin studies dendritic cell maturation and antigen processing, which represent anextension of her postdoctoral training where she described a novel pathway affecting theturnover of surface complexes of major histocompatibility-peptide complexes at the surface ofthe dendritic cells, a process which was regulated by ubiquitination. She is continuing studies ofdendritic cells with an emphasis on cells collected from the human lung. She published amanuscript addressing the role of ubiquitination in controlling MHC class II surface distributionon antigen presenting cells. A manuscript describing the unexpected finding that IgE receptor ondendritic cells promotes serum IgE clearance, was reviewed positively at the Journal of ClinicalInvestigation and is under revision. A third manuscript describing the role of ubiquitination inthe process of dendritic cell of thymic regulatory T cells was reviewed positively and is beingrevised for the Journal of Experimental Medicine. Two additional manuscripts are inpreparation. She was invited to present her work at a Keystone Meeting on Dendritic CellBiology.Dr. Shin supports her laboratory with two young investigator awards from the CancerResearch Institute and from the American Heart Association. She is re-submitting an R01 to theNIH for the next deadline after closely missing the payline on her first submission. She receiveda UCSF School of Medicine Bridge Fund Award, which is awarded to individuals whose grantsare felt most likely to succeed if given support for re-submission, at the start of 2013.Dr. Shin has established close collaborations with pulmonary physicians in the AirwayClinical Research Center – Drs. Paul Wolters, Prescott Woodruff and John Fahy – to obtainfreshly dissected human lung tissues from transplant procedures and samples of biopsies and celllavages from asthma patients and individuals with idiopathic pulmonary fibrosis. She is alsousing humanized transgenic mice with human FcεRI expressed on mouse cells in a patternresembling its expression in humans (developed in the Kinet lab at Harvard). Dr. Shin worksclosely with the Airway Clinical Research Center, the Flow Cytometry Core and the ImagingCenter. She currently has a graduate student, two postdoctoral trainees and a technician in herlaboratory.Dr. Allen began 5 years ago as a UCSF Fellow and is the first member of the UCSF FellowsProgram (http://biochemistry.ucsf.edu/~ucsffellows/current.html) who was selected to work on aspecific human disease, in this case, asthma. Dr. Allen combines skills in cellular and molecularimmunology with optical imaging capacities that have powered new insights in allergicinflammation. His primary research focuses on understanding the mechanisms by which highaffinityIgE-producing B cells and plasma cells are produced. Surprisingly, this remains a poorlyunderstood pathway of fundamental importance to the pathogenesis of allergy and asthma. Dr.Allen published some of his initial findings in a report in Immunity reporting his discovery thatIgE heavy chains inherently drive movement of B cells out of germinal centers, a process thatmay serve to limit somatic hypermutation and thus affinity. This finding will drive newhypotheses regarding mechanisms by which some allergic individuals develop high-affinity IgE,and constitute major efforts of his laboratory. His generation of an IgE reporter mouse thatpermits the efficient tracking of IgE-switched B cells constitutes an important technical advance5

for the field. He was invited to two Keystone meetings to present his findings. He continues towork closely with other investigators in the SABRE Center as he optimizes lung and immunecell imaging technologies that are applicable to broader use by other investigators on campus.Dr. Allen has attracted substantial new extramural funding to support his studies. Thisincludes an NIH R01 that will focus on imaging of basophils in tissues in situ and an NIHDirector’s New Innovator Award, fewer than 8% of which were funded in the last year.Together, these awards, both for 5 years duration, will bring in over $500K in direct costs tosupport his lab over the coming year.In recognition of these accomplishments, Dr. Allen was recruited to the CardiovascularResearch Institute (CVRI) at UCSF, where he joined the UCSF faculty as an Assistant Professorin the Department of Anatomy in 2013. He remains committed to investigations into the basicpathogenesis of asthma. Dr. Allen will continue to be a member of SABRE, and will continue toparticipate in monthly and quarterly meetings with SABRE investigators on the Parnassus site.Core ActivitiesAn integral component of the SABRE Center has been support and guidance for advancedtechnology cores. The specific workings of these Cores and their achievements are detailedelsewhere in this report. The SABRE Center contributes to cores in Mouse Physiology (whichprovides both acute and chronic mouse models of allergic lung inflammation, includingchallenge with model antigens, fungal antigens and house dust mite antigens), FunctionalGenomics, Genetics, Flow Cytometry and Imaging, including video, two-photon, confocal andtotal internal reflection instruments. Our largest monetary support goes to the Mouse Physiologyand the Genetics Cores, which support small animal models and the collection of cohorts ofcarefully phenotyped families with asthma, respectively, in order to meet specialized needs ofimportance to asthma investigators. These cores continue to attract substantial use amonginvestigators across the campus as well as scientists in related fields, including inflammation,genetics and stem cell biology. The Animal Core contributed to 5 AAF studies from non-UCSFinvestigators over the past year and helped train investigators at the University of Arizona and atVirginia Commonwealth who have started to center such studies at those universities. TheGenetics Core has procured very large cohorts of Latino and African American families afflictedwith asthma for use genetic studies, and continues to participate in a number of multiinstitutionalstudies for genome-wide investigations and gene replicative studies. Dr. Burchard,the Core Director, has attained national prominence in recognition of this highly annotatedcohort. The remaining cores are supported by smaller amounts of funding, typically to coredirectors and operators or to help support maintenance contracts for equipment, costs that aredifficult to recover through recharge or other mechanisms. The Imaging Core has made largetechnical strides in providing optical support for live lung and lymph node imaging. SABREfunding is concentrated on developing novel technologies to enhance live imaging capacity, toestablish site-specific photo-ablation technology and to extend imaging capacity to sections ofhuman lung. Participation in the Imaging Center has grown to support over 166 users involving66 Principle Investigators from 26 different Department or Organized Research Units at UCSF.Substantial training of new users and software development to support these new technologies is6

an ongoing part of the mission. Thus, in a relatively short time, the Imaging Core has become anintegral and productive component of the scientific community at UCSF. The FunctionalGenomics Core, led by Dr. David Erle, has used SABRE support to enable improvedtechnologies for high throughput sequencing, CHIP-seq, microRNA profiling and RNAseq. Thishas proven particularly useful in Dr. Ansel’s studies in identifying important regulatory RNAsinvolved in T cell fate and effector function.SABRE support for these technology cores has been leveraged to attract NIH funding: theAnimal Physiology Core is additionally supported by technical core funds from NIAID Asthmaand Allergic Disease Cooperative Research Center (Sheppard, Krummel, Woodruff, Erle) andthe Imaging Core is additionally supported by technical core funds supported by a PPG fromNHLBI to assess the microenvironments induced by lung inflammation (Caughey, Krummel,McDonald). In each case, funds from the SABRE Innovative Grants program initiated projectsthat led to the organization and support for these programmatic awards, indicative of the leverageenabled by a focused efforts from relatively small groups of investigators. Support for the FlowCytometry Core, which is largely self-supported and self-operated, is restricted to financial helpwith maintenance contracts, data base management and emergency laser failure, issues that areincompletely covered through recharge or grant-based mechanisms.These Cores achieve substantial leverage of resources, and over the past 2 years contributedto at least 12 successfully funded extramural grants, 7 postdoctoral fellowships and over 40 peerreviewedmanuscripts. Recharge systems have been set in place for the Functional GenomicsCore, the Mouse Physiology Core and the Flow Cytometry Core, and these are constantlyreassessed to ensure that fiscal accountability is maintained such that these services are not onlysustained, but enhanced by upgrading and enabling new technologies.Airway Clinical Research CenterThe Airway Clinical Research Center (ACRC) (see Figure) is a customized space of 3500 sqft. located on the 13 th floor of the UCSF Medical Center. The Airway Center comprises 5separate testing rooms for history and physical examination, phlebotomy, allergen skin tests,spirometry and methacholine challenge. This center also has a research bronchoscopy suite, asample processing lab, and administrative space for twelve research coordinators and sixresearch fellows. All of this space is dedicated to clinical research in airway disease; there is noclinical patient activity in this space. The Airway Clinical Research Center has fully equippedexam rooms for conducting pulmonary function testing, research bronchoscopy, participantinterviews and specimen collection and processing.7

The ACRC is equipped to see patients and collect tissue specimens quickly and efficiently.The following instruments are currently on site.Spirometers: Eight spirometers (Jaeger Masterscope (2), nSpire HDpft 1000 (1), SensormedicsVMax22 (1), Medgraphics CPFS/D Spirometer (2), nSpire KoKo PFT (2).Bronchoscopy equipment: Pentax Fiberoptic Bronchoscope Model #EB-1530T3 (2), PentaxProcessor Model #EPM-3500, Welch Allyn ProPaq CS vital signs monitor.Sputum Induction: Devilbiss UltraNeb 99 ultrasonic nebulizer (2), Nouvag UltraNeb ultrasonicnebulizer (2), NuAire NU-810-SPEC Biohood sputum induction booths (2).Biospecimen Processing room: Smith Kline Beecham VanGuard V6500 centrifuge, FisherScientific centrifuge Model #228, Thermo Shandon Cytospin 4 cytocentrifuge, Reicherthemocytometer (2), Eppendorf 5810R refrigerated centrifuge, Lab Companion B5-06 shakingwater bath, Fisher Scientific specimen refrigerator #97-915-1, Frigidaire refrigerator/freezer formedication storage, Sanyo -80 freezer MDF-U53VA, Sanyo -80 freezer MDF-U73VC, FormaClass II A2 Biological Safety Cabinet, TLS2200 Thermal Labeling System, barcode reader (2),Van Guard microscope.Other: Devilbiss PulmoAide compressor nebulizer (Rooms 1333, 1329A, 1329E), IsoTemp 205water bath, Fisher Scientific Stereomaster Zoom Microscope Model #12-562-1, Niox Mino nitricoxide (NO) monitor, ECG machines (2) HP Pagewriter Xli and Burdick Eclipse LE, Nellcorpulse oximeter (2), Welch Allyn Sure Temp Plus (2), SM DSM-2 micro-dosimeter, Salter LabsDosimeter (2), Tanita Scale, stadiometer, Bedfont Micro+ Smokerlyzer carbon monoxide (CO)monitors (2), Omron HEM-907XL blood pressure monitor.The ACRC has 12 research coordinators, a part time nurse, and a data manager. The modelfor these staff is that individual coordinators take ownership of specific research studies and8

manage that study in terms of recruitment, study visits, and biospecimen handling. Weeklymeeting of Airway Research Center staff and faculty involve presentations of specific projectsand administrative and quality assurance meeting focused on compliance with local, state, andfederal regulations governing research in human subjects.The ACRC enables approximately 1200 subject visits per year.The ACRC supports four large NIH research programs that involve multicenter networkcollaborations in asthma and COPD, thus supporting large numbers of patient visits per year:(i) AsthmaNet - U10 HL098107 (Boushey, Lazarus, Cabana [Pediatrics])(ii) Severe Asthma Research Program (SARP) - 1U10HL109146-01 (Fahy).(iii) COPD Clinical Research Network (CCRN) (Lazarus)(iv) SPIROMICS (Woodruff) - N01-08-08, The goal of this study is to identify sub-populationsand intermediate outcome measures in COPD (chronic obstructive pulmonary disease) through alarge multi-center longitudinal study.The Center also supports the clinical components of multiple other NIH awards involved withvarious aspects of the SABRE Center, including:(i) 1P01HL107202 (Fahy) 8/1/12 - 6/30/17NIH/NHLBI. Program Project Grant. Innate and Adaptive Immune Responses in Th2-highAsthma. Fahy, Ansel, Woodruff, Locksley.(ii) 2U19AI077439-06 (Sheppard) 4/1/13 - 3/31/18NIH/NIAID. Asthma and Allergic Diseases Cooperative Research Centers (AADCRC). IL-13and IL-17 dynamics in the asthmatic airway - Sheppard, Woodruff, Krummel, Erle.(ii) 5R01 HL080414-05 (Fahy) 7/1/5-5/31/15NIH/NHLBI. Protein carbohydrate interactions in the pathophysiology of acute asthmaexacerbations.(iii) Inner City Asthma Consortium (Boushey) – a part of NIH Asthma-Net.(iv) 1P50HL107191-01 (Fahy) 4/1/11- 3/31/13NIH/NHLBI. Preventing fucose-dependent binding of aspergillus and pseudomonas to lungmucin(v) 1 R01 HL097591 (Woodruff, PG) 7/1/09 - 06/30/13NIH/NHLBI. Role of Th2 and non-Th2 Inflammation in Airway Smooth Muscle Remodeling inAsthma.In addition to NIH grants, the ACRC is a resource for industry supported clinical research in9

airway disease at UCSF. Recent industry sponsors have included Genentech, BoehringerIngelheim, and Roche and research alliances with Gilead and Pfizer are pending. The hope is toexpand this aspect of SABRE-industry interactions as a platform for successful movement oftarget identification and pathophysiology onwards to drug and therapeutic developmentpathways.SABRE Center core scientists and the Director meet quarterly with Dr. Fahy and colleaguesto further communication, planning and collaborative investigations of human asthma patients.Each of the core scientists is already involved in ongoing or planned investigations withtranslational physician scientists in the ACRC, confirming that this will serve as an importantintegrative unit for translational interests of the SABRE Center. There is also a monthly researchconference for SABRE/ACRC investigators at the Parnassus site to promote interactions andcollaborations.Successful competition for extramural supportEvidence-based metrics for success will be important in leveraging continuing support in thefuture, including from philanthropic entities. Fund-raising will require evidence for metrics ofsuccess, including our capacity to attract extramural research dollars to the community, tocontribute high-impact papers that establish novel paradigms in the asthma research arena, toattract new investigators into the field and, ultimately, to drive the discovery of new therapiesthat affect the disease. Although therapeutic discoveries will take time, we believe we can pointto successes in these evidence-based metric achievements over this past year.Since the initial recruitment of Dr. Liu and the additions of Drs. Ansel, Shin and Allen, wehave seen a steady climb in the amounts of external funds accrued by the core five SABREinvestigators in support of their research efforts. This has occurred despite the difficult fundingclimate, and attests to the capacity of the Center to serve as a nidus for successful asthma basicresearch. As demonstrated by our ability to obtain a Program Project this year by capitalizing onthe access and expertise of colleagues in the Airway Clinical Research Center, we believe thatbuilding multicomponent research teams to take on difficult problems associated with asthmawill prove a successful strategy for maintaining this funding momentum.10

Growth in accumulated extramural funds by the five core SABRE investigatorsIn addition, activities related to the SABRE Center resulted in publication of numerousmanuscripts and contributions to many successfully awarded grants and fellowships of varioustypes to investigators at UCSF. These are catalogued in the individual Core and ProgramReports.Highlighted SABRE Center-supported papers with impact on asthma-related research in 2012-13Cheng LE, K Hartman, A Roers, MF Krummel, RM Locksley. 2013. Perivascular mast celldynamically probe cutaneous blood vessels to capture IgE. Immunity 38:166-175.Although cross-linking of IgE bound to high-affinity receptors on mast cells and basophilshas been associated with the acute pathology of allergy and asthma, the mechanism by whichtissue mast cells acquire serum IgE remains unclear. Using molecularly designed reagents andlive tissue imaging, this manuscript demonstrates that mast cells positioned along smallcutaneous blood vessels can extend elongated cellular processes between endothelial capillarycells into the blood stream, where they can extract IgE directly upon binding to surface IgEreceptors. Efforts are underway to discover the molecular determinants of this probing behaviorin hopes of uncovering new strategies for blocking this process that is central to allergichypersensitivity.Seumois G, P Vijayanand, CJ Eisley, N Omran, L Kalinke, M North, AP Ganesan, LJ Simpson,N Hunkapiller, F Moltzahn, PG Woodruff, JV Fahy, DJ Erle, R Djukanovic, R Blelloch, KM11

Ansel. 2012. An integrated nano-scale approach to profile miRNAs in limited clinical samples.Am J Clin Exp Immunol 1:70-89.Clinical research is limited by the amounts of material and the heterogeneity of specimensavailable for study. Standardized methods applicable to analysis of small amounts of materialare needed. The manuscript demonstrates a flow cytometric and nano-scale quantitative reversepolymerase chain reaction method that is capable of accurately and reproducibly measuringmicroRNAs from as few as 100 cells collected in bronchial biopsy specimens from asthmapatients obtained in the UCSF Airway Clinical Research Center. The study provides methodsthat should be applicable to other complex human diseases.Kudo M, AC Melton, C Chen, MB Engler, KE Huang, X Ren, Y Wang, X Berstein, JT Li, KAtabai, X Huang, D Sheppard. 2012. IL-17A produced by αβ T cells drives airway hyperresponsivenessin mice and enhances mouse and human airway smooth muscle contraction.Nature Medicine 18:547-54.The role of IL-17, a cytokine that serves to attract neutrophils to sites of inflammation, inasthma is of increasing interest as clinicians begin to understand non-allergic forms of asthma.Using both mouse and human tissues, the authors here show that IL-17A produced by CD4 Tcells in the lung can directly mediate airway smooth muscle hyper-contractility and expose amechanism related to smooth muscle myosin responsiveness. This study will drive much interestin understanding whether targeting this cytokine or these cells may comprise a therapeuticstrategy in some patients with non-allergic asthma.Thornton EE, Looney MR, O Bose, D Sen, D Sheppard, RM Locksley, X Huang, MF Krummel.2012. Spatiotemporally separated antigen uptake by alveolar dendritic cells and airwaypresentation to T cells in the lung. J Exp Med 209:1183-1199.How allergens are sampled and processed in the airways is not currently understood. Usinggenetically altered mice with fluorescent cells and two-photon intravital imaging of the lung, thismanuscript demonstrates that inhaled antigens are collected by probing dendritic cells in distalairway spaces, but these cells then migrate proximally to present processed antigen to T cells atbranch points along the conducting airways. This finding contributes to our understanding ofthe pathologic processes that center the pathology of asthma on the conducting airways ratherthan the more distal air-exchange portions of the lung.Yang Z, BM Sullivan, CDC Allen. 2012. Fluorescent in vivo detection reveals that IgE+ B cellsare restrained by an intrinsic cell fate predisposition. Immunity 36:857-72.Despite the importance of IgE in mediating manifestations of atopy, methods for studying theB cells that produce IgE were lacking, thus precluding the examination of this pathway as apotential strategy for intervention. The authors devised a knockin reporter mouse strain thatreveals cells that have productively switched the immunoglobulin locus to produce IgE. Afterconfirming that they can now isolate and image IgE-producing B cells in vitro, the authors makethe unexpected observation that IgE B cells mature in germinal centers, in contrast to priordogma, but that expression of a successfully rearranged IgE BCR leads to immediateupregulation of Blimp-1 and egress from the germinal center to become a memory B cell orplasma cell. This study reveals a cell-intrinsic mechanism that serves to limit the extent of12

somatic hypermutation, and hence affinity maturation, which occurs once a B cell expresses IgE.The possibility that patients with severe atopy might dysregulate this highly controlled pathwayis being explored.Organization of the body of this Annual ReportAs in prior years, we will organize this report by reviewing the SABRE Center activities andupdating the core technologies that focus on asthma-related research. We will summarize ourinteractions with other campus asthma-oriented research projects and provide listings of theseminar speakers of conferences to which we lend support. We will follow this with a listing ofthe newly funded, pending or submitted grants and publications since the prior annual reportsthat reflect support from the many SABRE Center activities. We will summarize the FinancialReport for the Program. Finally, we will outline the strategies for the coming years and appendthe current biographical summaries of the members, awardees and participants in the SABRECenter at UCSF.We wish to thank the Sandler family for their vision and support in creating and sustainingthe SABRE Center. Support for high-risk, open-ended, basic science is difficult to procure in thecurrent funding and fiscal climate. As noted in the overview above, we can identify manyexamples where support from the SABRE Center has been leveraged greatly to achievesubstantial gains for the scientific and academic study of asthma at UCSF. We are most gratefulfor the Sandlers’ continued support.13

Executive CommitteeRichard M. Locksley, M.D.The goals of the SABRE Center are to drive innovation in basic asthma research. Weapproach this goal by establishing a core basic science group dedicated to the study ofasthma, by promoting access to state-of-the-art technologies required to drive theresearch, by integrating their accomplishments across the greater UCSF campus, and bycreating opportunities for interactions with translational and clinical investigatorsstudying asthma patients. The Committee includes Dr. John Fahy, the Director of theAirway Clinical Research Center at UCSF, who continues to facilitate interactionsbetween SABRE members and the activities of the Clinical Research Center. TheExecutive Committee is constituted to provide the Director with counsel regarding issuesof scope, direction and execution. The Executive Committee played a major role in therecruiting faculty to the SABRE Center and provides oversight in sustaining progresstowards the overall goals of the Center.SABRE Center Executive Committee MembersRichard Locksley, M.D., ProfessorDirector, SABRE CenterDepartments of Medicine and Microbiology/ImmunologyHomer Boushey, M.D., ProfessorDepartment of MedicineHal Chapman, M.D., ProfessorDepartment of MedicineJohn V. Fahy, M.D., ProfessorDepartment of MedicineWilliam Seaman, M.D., ProfessorDepartment of MedicineDean Sheppard, M.D., ProfessorDepartment of MedicineArt Weiss, M.D., Ph.D., ProfessorDepartments of Medicine and Microbiology/ImmunologyZena Werb, Ph.D., ProfessorDepartment of Anatomy

Sandler Asthma Basic REsearch CenterScientific Advisory BoardSCIENTIFIC ADVISORY BOARD15

Sandler Asthma Basic REsearch CenterPhilippa (Pippa) Marrack, Ph.D.Professor of Molecular Biology and ImmunologyVice Chair, Department of ImmunologyNational Jewish Medical and Research Center, DenverProfessor at the Health Sciences Center, University of ColoradoResearch Investigator at the Howard Hughes Medical Institute, USAAs one of the world’s leading research scientists investigating T cells, the family of cellsthat help the body fight off disease, Dr. Marrack’s work has led to a greaterunderstanding of their role in the immune system.Born in the United Kingdom, Philippa Marrack earned her undergraduate and doctoraldegrees in biological sciences from the University of Cambridge. She left the UK in 1971to do postdoctoral work in the USA, where she has lived and worked ever since, initiallyat the University of California, and then at the University of Rochester. Since 1979, shehas been based in Denver, Colorado, where she is now a research investigator at theHoward Hughes Medical Institute, Vice Chair of the Department of Immunology andProfessor at National Jewish Medical and Research Center, and Professor at theUniversity of Colorado’s Health Sciences Center.During her career, Philippa Marrack has published more than 300 peer-reviewed journalarticles and she has served on the editorial boards of numerous journals, including Cell,Science, and the Journal of Immunology. Amongst her many honors are the RoyalSociety’s Wellcome Foundation Prize (1990), the Paul Ehrlich and Ludwig DarmtsädterPrize (1993) and the Louisa Gross Horwitz Prize (1995). She has served on variouspanels and boards for the American Cancer Society, the U.S. National Institutes ofHealth, and the Burroughs Wellcome Fund. She was the President of the AmericanAssociation of Immunologists in 2000-2001, and is currently the President of theInternational Union of Immunological Societies.17

Sandler Asthma Basic REsearch CenterChristopher Wilson, M.D.Director, Global Health Discovery Program, Gates FoundationDr. Chris Wilson, Director of the Global Health Discovery program, leads a team thattargets fundamental scientific and technological advances in global health that could leadto new ways to prevent, treat, and diagnose disease.Wilson joined the foundation in 2009 as Deputy Director, Vaccine Discovery and HumanBiology, Global Health Discovery.Wilson is a pediatrician and immunologist. He joined the faculty at the University ofWashington in 1979 in the Infectious Diseases Division of the Department of Pediatricsand later served as head of the Division of Infectious Diseases, Immunology andRheumatology. In 1989, he became one of the founding faculty members in the newDepartment of Immunology, and served as Chairman of the Department of Immunologyand head of the graduate program in immunology from 1999-2009.He has also served on a number of national advisory panels, including the Institute ofMedicine Vaccine Safety Review Committee (2001-2004) and the National AdvisoryCouncil on Child Health and Human Development, NICHD, NIH, and he co-chaired theNIAID US Immunodeficiency Network Pilot Grant Review Committee. He is an electedfellow of the American Association for the Advancement of Science.Wilson received a bachelor’s degree from the University of California, Irvine and amedical degree from UCLA. He trained in pediatrics at Boston Children’s Hospital/Harvard Medical School, served in the US Public Health Service, and then was a postdoctoralfellow in infectious diseases while performing immunology research at StanfordUniversity.18

Sandler Asthma Basic REsearch CenterSABRE CENTER INVESTIGATORS19

Sandler Asthma Basic REsearch CenterRichard M. Locksley, M.D.Professor, Departments of Medicine andMicrobiology & ImmunologyInvestigator, Howard Hughes Medical InstituteUCSF513 Parnassus AvenueMedical Sciences, S-1032B, Box 0795San Francisco, CA 94143-0795Tel: 415-476-3087Fax: 415-502-5081Website: Cancer CenterImmunology Graduate ProgramPulmonary & Critical Care DivisionHoward Hughes Medical InstituteVirology & Microbial PathogenesisDr. Locksley is the Director of the Sandler Asthma Basic Research Center (SABRE) anda Howard Hughes Medical Institute Investigator. He is a Professor in the Departments ofMedicine and Microbiology & Immunology. He received his undergraduate degree inbiochemistry from Harvard and his M.D. from the University of Rochester. Aftercompleting his residency at UCSF, he trained in infectious diseases at the University ofWashington. Prior to his position as director of the SABRE Center, Dr. Locksley served18 years as the Chief of the Division of Infectious Diseases at UCSF Medical Center. Dr.Locksley is a fellow of the American Academy of Arts and Sciences.Dr. Locksley's laboratory focuses on mechanisms by which the immune system becomesorganized in stereotyped ways against discrete types of challenges. This involves thedifferentiation of naïve helper T cells to distinct types of subsets that produce differentkinds of cytokines, key effector molecules of the immune system. In turn, these differentT cells subsets work with different kinds of innate cells, including neutrophils,eosinophils, macrophages and others, to mediate immunity. Properly executed, suchresponses mediate protection against infectious organisms or repair of damaged tissues,but, when dysregulated, these immune responses lead to disease, including asthma.Dr. Locksley’s laboratory investigates immunity using mice genetically engineered toreport cytokines expressed during the different types of immune responses. Thisapproach reveals the shared expression of important cytokines by both innate andadaptive immune cells. Using these methods, the laboratory participated in recentdiscoveries of innate lymphoid type 2 cells, which represent a previously unstudied cellnow implicated in allergic immunity. The laboratory also revealed a novel mechanism bywhich cutaneous mast cells capture IgE from blood. The laboratory continues to studythe role of chitin, a structural component of many allergens – including dust mites,cockroaches, shellfish and molds – as well as helminthes, in inducing infiltration of cells20

Sandler Asthma Basic REsearch Centerinvolved in allergy into tissues, and to pursue recent finding connecting the cells ofallergic immunity with metabolic pathways involved in vertebrate homeostasis.Representative Publications1. Reese TA, H-E Liang, AM Tager, AD Luster, N van Rooijen, D Voehringer, RMLocksley. 2007. Chitin induces accumulation in tissue of innate immune cellsassociated with allergy. Nature 447:92-6.2. Reinhardt RL, HE Liang, RM Locksley. 2009. Cytokine-secreting follicular Tcells shape the antibody repertoire. Nature Immunol 10:385-393.3. Sullivan BM, RM Locksley. 2009. Basophils: a nonredundant contributor tohost immunity. Immunity 30:12-20.4. Siebold MA, TA Reese, S Choudhry, MT Salam, K Beckman, C Egn, A Atakilit,K Meade, M Lenoir, HG Watson, S Thyne, R Kumar, KB Weiss, LC Grammar, PAvila, RP Schleimer, JV Fahy, J Rodriguez-Santana, W Rodriguez-Cintron, RGBoot, D Sheppard, FD Gilliland, RM Locksley, EG Burchard. 2009. Differentialenzymatic activity of common haplotypic versions of the human acidicmammalian chitinase protein. J Biol Chem 284:19650-8.5. Locksley RM. 2010. Asthma and allergic inflammation. Cell 140:777-83.6. Price AE, HE Liang, BM Sullivan, RL Reinhardt, CJ Eisley, EJ Erle, RMLocksley. 2010. Systemically dispersed innate IL-13-expressing cells in type 2immunity. Proc Natl Acad Sci USA 107:11489-94.7. Wu D, AB Molofsky, HE Liang, RR Ricardo-Gonzalez, HA Jouihan, JK Bando,A Chawla, RM Locksley. 2011. Eosinophils sustain adipose alternativelyactivated macrophages associated with glucose homeostasis. Science 332:243-7.8. Sullivan BM, H-E Liang, JK Bando, D Wu, LE Cheng, JK McKerrow, CDCAllen, RM Locksley. 2011. Genetic analysis of basophil function in vivo.Nature Immunol 12:527-35.9. Nguyen KD, Y Qui, X Cui, YP Sharon Goh, J Mwangi, T David, L Mukundan, FBrombacher, RM Locksley, A Chawla. 2011. Alternatively activatedmacrophages produce catecholamines to sustain adaptive thermogenesis. Nature480:104-8.10. Liang H-E, RL Reinhardt, JK Bando, BM Sullivan, I-C Ho, RM Locksley. 2011.Divergent expression patterns of IL-4 and IL-13 define unique functions inallergic immunity. Nature Immunol 13:58-66.11. Cheng LE, K Hartmann, A Roers, MF Krummel, RM Locksley. 2013.Perivascular mast cells dynamically probe cutaneous blood vessels to capture IgE.Immunity 38:166-75.12. Van Dyken SJ, RM Locksley. 2013. Interleukin-4- and interleukin-13-mediatedalternatively activated macrophages: role in homeostasis and disease. Annu RevImmunol 31:317-43.13. Molofsky AB, JC Nussbaum H-E Liang, SJ Van Dyken, LE Cheng, A Mohapatra,A Chawla, RM Locksley. 2013. Innate lymphoid type 2 cells (ILC2) sustainvisceral adipose tissue eosinophils and alternatively activated macrophages. JExp Med (in press).21

Sandler Asthma Basic REsearch CenterChristopher D. C. Allen, Ph.D.Assistant ProfessorCardiovascular Research InstituteDepartments of Anatomy and Microbiology and ImmunologySandler Asthma Basic Research Center513 Parnassus Ave. Box 0414, HSE-205ASan Francisco, CA 94143-0414Tel: 415-476-5178Fax: 415-502-4995Dr. Allen is an Investigator of the Cardiovascular Research Institute and an AssistantProfessor in the Departments of Anatomy and Microbiology and Immunology at UCSF.He completed his B.S. in Biology at MIT, and then his Ph.D. at UCSF in the BiomedicalSciences Graduate Program in the laboratory of Jason Cyster, with the support of aHoward Hughes Medical Institute Predoctoral Fellowship. Dr. Allen was then selected asthe first Sandler-Newmann Foundation UCSF Fellow in Asthma Research, giving himthe opportunity to attain principal investigator status and to develop an independentresearch program in asthma immediately after obtaining his Ph.D. He was recently hiredinto a tenure-track Assistant Professor position at UCSF.Dr. Allen’s research in the SABRE center focuses on the cellular immune response inasthma. He is using his expertise in cutting-edge two-photon microscopy to visualizeinteractions among cells in the lungs as well as in lymphoid organs that ‘prime’ cells forimmune responses in the respiratory tract. A particular emphasis of his research is on thedevelopment and function of IgE antibodies that contribute to allergic responses. IgE hasbeen shown to be important in human asthma, yet little is known about the events leadingto IgE production after inhaling allergen. The major goals of the research are to:1) Develop innovative new mouse models of asthma that will be useful for studies ofIgE antibody responses to inhaled allergens.2) Define the early events leading to allergic sensitization and IgE antibodyproduction after inhalation of allergen.3) Characterize the interactions among inflammatory cells in the lung in asthma anddefine the features of the microenvironments in which these interactions occur.Publications1. Allen C.D.C., Ansel K.M., Low C., Lesley R., Tamamura H., Fujii N. Cyster J.G.(2004). Germinal center dark and light zone organization is mediated by CXCR4and CXCR5. Nature Immunology, 5(9), 943-952.2. Chen T.T., Li L., Chung D.H., Allen C.D.C., Torti S.V., Torti F.M., Cyster J.G.,Chen C.Y., Brodsky F.M., Niemi E.C., Nakamura M.C., Seaman W.E., Daws22

Sandler Asthma Basic REsearch CenterM.R. (2005). TIM-2 is expressed on B cells and in liver and kidney and is areceptor for H-ferritin endocytosis. The Journal of Experimental Medicine,202(7), 955-965.3. Allen C.D.C., Okada T., Tang H.L., Cyster J.G. (2007). Imaging of germinalcenter selection events during affinity maturation. Science, 315(5811), 528-531.4. *Allen C.D.C., *Okada T., *Cyster J.G. (2007). Germinal-center organizationand cellular dynamics. Immunity 27(2), 190-202. *co-corresponding author.PMCID: PMC2242846.5. Haynes N.M., Allen C.D.C., Lesley R., Ansel K.M., Killeen N., and Cyster J.G.(2007). Role of CXCR5 and CCR7 in follicular Th cell positioning andappearance of a programmed cell death gene-1 High germinal center-associatedsubpopulation. The Journal of Immunology, 179(8), 5099-5108.6. *Allen C.D.C., *Cyster J.G. (2008). Follicular dendritic cell networks of primaryfollicles and germinal centers: phenotype and function. Seminars in Immunology20(1), 14-25. *co-corresponding author PMCID: PMC2366796.7. Beltman J.B., Allen C.D.C., Cyster J.G., de Boer R.J. (2011). B cells withingerminal centers migrate preferentially from dark to light zone. Proceedings ofthe National Academy of Sciences, 108(21), 8755-8760. PMCID: PMC31023848. Green J.A., Suzuki K., Cho B., Willison L.D., Palmer D., Allen C.D.C., SchmidtT.H., Xu Y., Proia R.L., Coughlin S.R., Cyster J.G. (2011). The sphingosine 1-phosphate receptor S1P 2 maintains the homeostasis of germinal center B cells andpromotes niche confinement. Nature Immunology, 12(7), 672-680. PMCID:PMC3158008.9. Sullivan B.M., Liang H.E., Bando J.K., Wu D., Cheng L.E., McKerrow J.K.,*Allen C.D.C., *Locksley R.M. (2011). Genetic analysis of basophil function invivo. Nature Immunology, 12(6), 527-535. *co-corresponding author. PMCID:PMC3271435.10. Steiner D.F., Thomas M.F., Hu J.K., Yang Z., Babiarz J.E., Allen C.D.C.,Matloubian M., Blelloch R., Ansel K.M. (2011). MicroRNA-29 Regulates T-BoxTranscription Factors and Interferon-γ Production in Helper T Cells. Immunity,35(2), 169-181. PMCID: PMC3361370.11. Yang Z., Sullivan B.M., Allen C.D.C. (2012). Fluorescent in vivo detectionreveals that IgE + B cells are restrained by an intrinsic cell fate predisposition.Immunity, 36(5), 857-872.23

Sandler Asthma Basic REsearch CenterArron JR, Erle DJ, Woodruff PG. Airway Epithelial miRNA Expression isAltered in Asthma. Am J Respir Crit Care Med. 186:965-74 (2012)8. Thomas MF, Abdul-Wajid S, Panduro M, Babiarz JE, Rajaram M, Woodruff P,Lanier LL, Heissmeyer V, Ansel KM. Eri1 regulates microRNA homeostasis andmouse lymphocyte development and anti-viral function. Blood. 120:130-42(2012)9. Vijayanand P, Seumois G, Simpson LJ, Abdul-Wajid S, Baumjohann D, PanduroM, Huang X, Interlandi J, Djuretic IM, Brown DR, Sharpe AH, Rao A, AnselKM. Interleukin-4 Production by Follicular Helper T Cells Requires theConserved Il4 Enhancer Hypersensitivity Site V. Immunity 36:175-87 (2012).10. Baumjohann D, Okada T, Ansel KM. Cutting Edge: Distinct Waves of BCL6Expression during T Follicular Helper Cell Development. J Immunol.187:2089-92(2011)11. Steiner DF, Thomas MF, Hu JK, Yang Z, Babiarz JE, Allen CD, Matloubian M,Blelloch R, Ansel KM. MicroRNA-29 Regulates T-Box Transcription Factorsand Interferon-γ Production in Helper T Cells. Immunity 35:169-81 (2011)12. Sofi MH, Qiao Y, Ansel KM, Kubo M, Chang CH. Induction and Maintenance ofIL-4 Expression Are Regulated Differently by the 3' Enhancer in CD4 T Cells. J.Immunol. 186:2792-9 (2011)13. Thomas MF, Ansel KM. Construction of small RNA cDNA libraries for deepsequencing. Methods Mol Biol. 667:93-111 (2010)14. Ansel KM*, Pastor WA, Rath N, Lapan AD, Glasmacher E, Wolf C, Smith LC,Papadopoulou N, Lamperti E, Tahiliani M, Ellwart JW, Shi Y, Kremmer E, RaoA, Heissmeyer V*. Mouse ERI-1 interacts with the ribosome and catalyzes 5.8SrRNA processing. Nat Struct Mol Biol. 15:523-30 (2008) (*correspondingauthors)15. Thai TH, Calado DP, Casola S, Ansel KM, Xiao C, Xue Y, Murphy A,Frendewey D, Valenzuela D, Kutok JL, Schmidt-Supprian M, Rajewsky N,Yancopoulos G, Rao A, Rajewsky K. Regulation of the germinal center responseby microRNA-155. Science 316:604-8 (2007)16. Djuretic IM, Levanon D, Negreanu V, Groner Y, Rao A, Ansel KM. T-bet andRunx3 cooperate to activate Ifng and silence Il4 in Th1 cells. Nat Immunol.8:145-53 (2007)17. Ansel KM, Djuretic I, Tanasa B, Rao A. Regulation of Th2 differentiation andthe IL4 locus. Annu Rev Immunol. 24:607-56 (2006)18. *Monticelli S, *Ansel KM, *Xiao C, *Socci ND, Krichevsky AM, Thai, T-H,Rajewsky N, Marks DS, Sander C, Rajewsky K, Rao A, Kosik KS. MicroRNAprofiling of the murine hematopoietic system. Genome Biol. 6:R71 (2005)19. *Muljo SA, *Ansel KM, *Kanellopoulou C, Livingston DM, Rao A, RajewskyK. Aberrant T cell differentiation in the absence of Dicer. J Exp Med. 202:261-9(2005).20. Ansel KM, Greenwald RJ, Agarwal SA, Bassing CH, Monticelli S, Interlandi J,Djuretic IM, Lee DU, Sharpe AH, Alt FW, Rao A. Deletion of a conserved Il4silencer impairs Th1-mediated autoimmunity. Nat Immunol. 5:1251-9 (2004).26

Limin Liu, Ph.D.Associate Professor, Department of Microbiology/ImmunologySandler Asthma Basic Research CenterUniversity of California San Francisco513 Parnassus Ave.HSE 201J, Box 0414San Francisco, CA 94143-0414Tel: 415-476-1466Fax: 415-476-8201email: Limin.Liu@ucsf.eduDr. Limin Liu is an Associate Professor in the Department of Microbiology & Immunology. Heobtained his B.S. in Biology from University of Science and Technology of China and his Ph.D.in Molecular Biology from University of Missouri. He did postdoctoral research on the biologyof nitric oxide (NO) at Duke University Medical Center.Dr. Liu’s laboratory focuses on enzymatic deactivation of NO bioactivity and its role in asthmaand other diseases. NO plays important roles in virtually every biological system. NO regulatesfunctions of numerous proteins through S-nitrosylation, the covalent addition of NO to cysteinethiol. Through the study of S-nitroso-glutathione reductase (GSNOR), the key protein for denitrosylationin cells, Dr. Liu and colleagues have demonstrated that S-nitrosylation and itsdeactivation exert critical functions in systematic inflammation, asthma, cancer, and many otherphysiological and pathological processes.GSNOR and asthma It has been demonstrated with GSNOR-deficient (GSNOR -/- ) mice thatincreased S-nitrosylation from GSNOR deficiency in a model of allergic asthma does not affectimmune responses but abolishes airway hyperresponsiveness. Dr. Liu’s laboratory isinvestigating the mechanism of S-nitrosylation-dependent protection to understand a keyquestion in asthma: How do allergic immune responses cause airway hyperresponsiveness?GSNOR and carcinogenesis NO is implicated in tumorigenesis by much circumstantialevidence, but little is known definitively about the mechanisms through which endogenous NOmight regulate the behavior of pre-cancerous or cancerous cells. Using GSNOR -/- mice Dr. Liu’slaboratory has discovered that dysregulated S-nitrosylation from GSNOR deficiency inactivates akey DNA repair system and promotes liver cancer (Science Translational Medicine 2:19ra13,2010). Investigation is underway to expend the findings and to further elucidate molecularmechanisms.New pathways in NO deactivation Dr. Liu and colleagues have demonstrated that GSNORand flavohemoglobin, the major NO-consuming enzyme, operate together to regulate NObioactivities and to protect against NO-related toxicity in the yeast Saccharomyces cerevisia.They are employing the yeast model to elucidate the roles of additional, novel genes that arerequired for protection against NO-related toxicity. Homologue proteins are also investigated inanimals.27

Selected Publications1. Liu L, Yan Y, Zeng M, Zhang J, Hanes MA, Ahearn G, McMahon TJ, Dickfeld T,Marshall HE, Que LG, Stamler JS (2004). Essential roles of S-nitrosothiols in vascularhomeostasis and endotoxic shock. Cell 116:617-628.2. Que LG, Liu L, Yan Y, Whitehead GS, Gavett SH, Schwartz DA, Stamler JS (2005).Protection from experimental asthma by an endogenous bronchodilator. Science308:1618-1621.3. Choudhry S, Que LG, Yang Z, Liu L, Eng C, Kim SO, Kumar G, Thyne S, Chapela R,Meade K, Watson HG, LeNoir M, Rodriguez-Santana JR, Rodriguez-Cintron W, AvilaPC, Stamler JS, Burchard EG (2010). GSNO Reductase and β2 Adrenergic ReceptorGene-gene Interaction: Bronchodilator Responsiveness to Albuterol. Pharmacogeneticsand Genomics 20:351-8.4. Wei W, Li B, Hanes MA, Kakar S, Chen X, Liu L (2010). Deficiency of S-Nitrosoglutathione Reductase Impairs DNA Repair and Promotes Hepatocarcinogenesis.Science Translational Medicine 2: 19ra13.5. Yang Z, Wang Z, Doulias P, Wei W, Ischiropoulos H, Locksley RM, Liu L (2010).Lymphocyte development requires S-nitrosoglutathione reductase. J Immunol, 185:6664-6669.6. Wei W, Yang Z, Tang CH, Liu L (2011). Targeted deletion of GSNOR in hepatocytes ofmice causes nitrosative inactivation of O6-alkylguanine-DNA alkyltransferase andincreased sensitivity to genotoxic diethylnitrosamine. Carcinogenesis 32:973–977.7. Na B, Huang ZM, Wang Q, Qi ZX, Tian YJ, Lu CC, Yu JW, Hanes MA, Sanjay KakaraS, Huanga EJ, Ou JHJ, Liu L‡,*, and Yen TSB‡,† (2011). Transgenic Expression ofEntire Hepatitis B Virus in Mice Induces Hepatocarcinogenesis Independent of ChronicLiver Injury. PLoS One 6:e26240.8. ‡co-senior author; *Corresponding author; †Deceased August 31, 2009.9. Tang CH, Wei W, Liu L (2012). Regulation of DNA Repair by S-Nitrosylation. BiochimBiophys Acta 1820:730–735.10. Ozawa K*, Tsumoto H, Wei W, Tang CH, Komatsubara AT, Kawafune H, Shimizu K,Liu L*, Tsujimoto G (2012). Proteomic analysis of the role of S-nitrosoglutathionereductase in lipopolysaccharide-challenged mice. Proteomics 12, 2024-2035.*Corresponding author.11. Leung J, Wei W, Liu L (2013). S-nitrosoglutathione reductase deficiency increasesmutagenesis from alkylation in mouse liver. Carcinogenesis (in press).12. Tang CH, Wei W, Hanes MA, Liu L (2013). Hepatocarcinogenesis driven by GSNORdeficiency is prevented by iNOS inhibition. Cancer Research (in press).28

Sandler Asthma Basic REsearch CenterJeoung-Sook Shin, Ph.D.Assistant Professor, Department of Microbiology & ImmunologySandler Asthma Basic Research CenterUniversity of California San Francisco513 Parnassus Ave, HSE-201San Francisco, CA 94143-0414Tel: 415-476-5451Fax: 415-476-3939email: jeoung-sook.shin @ ucsf.eduDr. Jeoung-Sook Shin is an Assistant Professor in the Department of Microbiology &Immunology. She completed her B.S. and M.S. in Chemistry at Seoul NationalUniversity, Korea. She received her Ph.D. from Duke University and her postdoctoraltraining at Yale University as a Jane Coffin Childs Memorial Fund Postdoctoral Fellow.The Shin laboratory is interested in understanding the molecular mechanism and functionof dendritic cell-mediated antigen presentation. Dr. Shin has previously found that theantigen-presenting molecule MHCII is ubiquitinated by MARCH1 ubiquitin ligase indendritic cells, and this ubiquitination mediates MHCII endocytosis and lysosomaldegradation. Her laboratory has recently found that the costimulatory molecule CD86 isalso ubiquitinated by MARCH1 and that this ubiquitination also mediates endocytosisand degradation of CD86. More recently, Dr. Shin’s laboratory has studied the functionalrole of this ubiquitination. This study indicates that MHCII ubiquitination is required forproper production of regulatory T cells (Tregs) in the thymus. Currently, Dr. Shin isinvestigating how MHCII ubiquitination contributes to Treg development and whetherTregs generated in MHCII ubiquitination-dependent manner are distinct in theirrepertoire or function.The Shin laboratory is also interested in understanding the role of the high affinity IgEreceptor FceRI expressed in dendritic cells. Although the role of FceRI in thepathogenesis of allergy is well-known, its physiologic role remains unclear. Dr. Shin’slaboratory has recently found that FceRI is constitutively endocytosed and transported tothe lysosomes in human dendritic cells and monocytes, and that this FceRIendolysosomal trafficking mediates cellular entry of circulating IgE contributing to serumIgE clearance. These findings suggest that FceRI expressed by dendritic cells andmonocytes may play an important role in regulating serum IgE concentration in humans.Her laboratory is currently investigating whether unusually high blood IgE levels foundin some human diseases is attributed to the alteration in FceRI endolysosomal traffickingthat results circulating IgE not efficiently entering cells but accumulating in the blood.Dr. Shin’s research programs are greatly benefited by many of the excellent core facilitiessupported by SABRE. Flow cytometry core is being used in a daily basis for most of theprojects. Microscopy facility is helping in situ analysis of dendritic cells in human tissues29

Sandler Asthma Basic REsearch Centerand also the analysis of protein distribution inside dendritic cells. Mouse physiology coreis being used to test the therapeutic potential of human IgE derivative that Dr. Shin hasrecently found to be immune-regulatory.Selected Publications1. Shin, JS, Shelburne, CP, Jin, C, LeFurgey, EA, Abraham, SN. Harboring ofparticulat allergens within secretory compartments by mast cells followingIgE/FcεRI-lipid raft mediated phagocytosis, J Immunol. 177:5791-5800, 20062. Shin, JS, Ebersold, M, Pypaert, M, Delamarre, L, Hartley, A, and Mellman, I.Surface expression of MHC class II in dendritic cells is controlled by regulatedubiquitination, Nature. 444:115-8, 20063. Bloom, O, Unternaehrer, JJ, Jiang, A, Shin, JS, Delamarre, L, Allen, P, andMellman, I. Spinophilin participates in information transfer at immunologicalsynapses, J Cell Biol. 181:203-11, 20084. Baravalle, G, Park, H, McSweeney, M, Ohmura-Hoshino, M, Matsuki, Y, Shin,JS. Ubiquitination of CD86 is a key mechanism in regulating antigen presentationby dendritic cells, J Immunology. 187:2966, 20115. Ma, JK, Platt MY, Eastham-Anderson, J, Shin, JS*, and Mellman, I*. MHCclass II distribution in dendritic cells and B cells is determined by ubiquitin chainlength, PNAS. 109:8820, 20126. *Shin, JS and Mellman, I contributed equally to this work30

Sandler Asthma Basic REsearch CenterCore FacilitiesCORE FACILITIES31

Sandler Asthma Basic REsearch CenterCore FacilitiesMouse Physiology and Morphology CoreDirector: Xiaozhu Huang, M.D.ObjectiveThe objective of the Sandler animal physiology and morphology core facility is to providesupport to investigators at UCSF and other research institutes for their asthma related research.The core facility has extensive experience in generating and analyzing variety of allergic animalmodels. Investigators gain insight to the molecular mechanisms of asthma development througheither full or partial service provided by the core laboratory. The core also provides training tostudents, technicians and post-doctoral fellows in techniques relevant to the animal models andtheir analysis.AccomplishmentsDuring the year 2012, the Animal Physiology and Morphology Core provided assistance to manyUCSF investigators, including Drs Mark Ansel, Kamran Atabai, Anthony deFranco, David Erle,Xiaozhu Huang, Limin Liu, Steve Nishmura, Jason Rock, Dean Sheppard and Art Weiss for theirprojects studying airway physiology, immunology, cell and molecular biology and other relatedareas. The service provided by the core lab has significant impacts on many of these asthmarelated projects.Dr. Dean Sheppard has been interested in studying biologic role of integrin α9β1, an integrinexpressed on airway smooth muscle, in asthma development. The core conducted lung functionstudies in mice lacking integrin α9β1 specifically in smooth muscle. These mice had increasedairway responsiveness in vivo, and loss or inhibition of integrin α9β1 also increased in vitroairway narrowing and airway smooth muscle contraction in murine and human airways.Contraction was enhanced in control airways by the higher-order polyamine spermine or by cellpermeablePIP2, but these interventions had no effect on airways lacking integrin α9β1 or treatedwith integrin α9β1-blocking antibodies. Enhancement of SSAT activity or knockdown ofPIP5K1γ inhibited airway contraction, but only in the presence of functional integrin α9β1.Therefore, integrin α9β1 appears to serve as a brake on airway smooth muscle contraction byrecruiting SSAT, which facilitates local catabolism of polyamines and thereby inhibits PIP5K1γ.Targeting key components of this pathway could thus lead to new treatment strategies forasthma. This work has been published in Journal of Clinical Investigation last year.The core assisted Dr. Rosemary Ahnkurst’s group in studying TGFβ activation and signaling inexperimental models of allergen-induced asthma as potential therapeutic targets. We show thatinnate variation within TGFβ1 genetic modifier loci, Tgfbm2 and Tgfbm3, alters diseasesusceptibility. Specifically, Tgfbm2(129) and Tgfbm3(C57) synergize to reverse accentuatedairway hyperresponsiveness caused by low TGFβ1 levels in Tgfb1(+/-) mice of the NIH/OlaHsdstrain and the epistatic interaction between Tgfbm2(129) and Tgfbm3(C57) uncouples theinflammatory response to ovalbumin from those of airway remodeling and airwayhyperresponsiveness, illustrating independent genetic control of these responses. The studysuggests that differential inheritance of genetic variants of Tgfbm genes alters biologicalresponses to reduced TGFβ1 signaling in an experimental asthma model and TGFβ antagonists32

Sandler Asthma Basic REsearch CenterCore Facilitiesfor treatment of lung diseases might therefore give diverse outcomes, dependent on geneticvariation. This work resulted in a publication last year in Proc Natl Acad Sci U S A.The animal physiology core also provides assistance to current as well as former AAF awardeesfor their asthma related studies. Continuing support of their asthma related projects has beenappreciated by many former awardees. Dr. Kenneth Rock is one of the former AAF awardeesand continues working on asthma related projects. To help solve one of variable allergen relatedoutcomes (Aspergillus induced pulmonary fibrosis) that his group has encountered, the coreperformed an Aspergillus sensitized and challenged experiment to prove that mice developsignificant lung fibrosis using this model. Dr. Rock’s group is currently working on the projectwith the helpful information provided by the core.In 2012, we continued our efforts in developing more regimens to suit the needs of investigators.One such effort was to use InExpose aerosol machine (Scireq, Canada) for OVA challenges.Our current intra-nasal OVA challenge has been working very well and produces consistentresults but it is not the natural route of sensitization and challenge. Some investigators haveexpressed interest of using aerosol route for challenge. We then tried 1% OVA aerosol challengeaccording to the literature but failed to achieve allergen-induced phenotype. We are in theprocess of trying different dosages and have just obtained preliminary data suggesting 6% OVAmay be sufficient to produce an allergen-induced airway hyperresponsiveness and lunginflammation.Training and Integration with Sandler ProgramThe core continues to provide training support for lab members whose PIs are interested inadapting the protocols and techniques that are useful for their studies. In 2012, investigators frommultiple laboratories (Labs from UCSF- Drs. Jeffery Cox and David Erle; other researchinstitutes - Dr. Michael Daines at University of Arizona, Dr. Daniel Conrad at VirginiaCommonwealth University) sent lab members to the core lab in observing the routineperformance and getting hands-on experience using the equipment and protocols. Jamie Sturgilland Jennifer Bradley from Virginia Commonwealth University made a special trip to visit us lastyear. They spent time observing core lab performing experiments and processing routinesamples, and obtained protocols used routinely by the core lab. Currently Dr. Conrad’s group hasbeen able to run lung function analysis in the studies of murine models of allergic asthma fortheir related studies. Core lab follows-up and communicates with former trainees the continuesthe information exchange that has benefitted studies for both sides.The animal core director attends the weekly UCSF pulmonary conference, monthly SABREmeeting, AAF and ATS annual meetings. This provides direct interaction between the animalcore and investigators who are interested in using the core service. The potential experiments canbe discussed and oftentimes can be arranged during the interaction.Future ActivitiesWe continually try to improve our techniques and develop allergic model regimens so that wemay accommodate the investigators needs. As mentioned above, we have been working on33

Sandler Asthma Basic REsearch CenterCore Facilitiesdeveloping protocol using the aerosol machine for allergen challenge. Our preliminary datasuggest that 6% OVA aerosol for 30 minutes once a day for 3 days may produce significantOVA-induced lung function change and lung inflammation. Further study is needed to validateour observation. We still need to improve the consistency and reduce the variability of our housedust mite model. We have been paying close attention to our key equipment. FlexiVent makesthe key lung function measurement possible. The machine model we are using has beendiscontinued and technical service will soon no longer be available. With the continuing supportfrom the SABRE foundation, the animal physiology and microscopy core facility will continueto provide UCSF investigators with high quality servicecritical to our research community.Grants and Publications:GrantThe animal physiology and morphology core continues to work with investigators at UCSF aswell as at other research institutes to provide consultations and support letters for their grantapplications. Core director generally meets in person (with local investigators) or has phoneconversations (with outside institutions) with grant applicants in helping them understand theprinciples of allergic animal models and carefully discuss the experimental protocols, animalnumbers and final outcomes. The AAF applicants very often have not worked with asthma, andsome not even with lung disease. For applicants who propose an in vivo animal experiment, abrief description of an allergic animal model will be provided so investigators can incorporate itinto their proposals. We not only help investigators funded by NIH, AAF and other grants butalso, if they are funded, make commitments to collaborate with investigators who submitproposals. The core staff receive direct salary support from Sandler foundation, NIAID and ourrecharge system.Publications1. Gordon ED, Sidhu SS, Wang ZE, Woodruff PG, Yuan S, Solon MC, Conway SJ, HuangX, Locksley RM, Fahy JV. A protective role for periostin and TGF-β in IgE-mediatedallergy and airway hyperresponsiveness. Clin Exp Allergy. 2012 Jan; 42(1):144-55.PMID: 220931012. Sugimoto K, Kudo M, Sundaram A, Ren X, Huang K, Bernstein X, Wang Y, RaymondWW, Erle DJ, Abrink M, Caughey GH, Huang X, Sheppard D. The αvβ6 integrinmodulates airway hyperresponsiveness in mice by regulating intraepithelial mast cells. JClin Invest. 2012 Feb 1; 122(2):748-583. Vijayanand P, Seumois G, Simpson LJ, Abdul-Wajid S, Baumjohann D, Panduro M,Huang X, Interlandi J, Djuretic IM, Brown DR, Sharpe AH, Rao A, Ansel KM.Interleukin-4 production by follicular helper T cells requires the conserved Il4 enhancerhypersensitivity site V. Immunity. 2012 Feb 24;36(2):175-874. Makoto Kudo, Andrew C. Melton, Chun Chen, Mary B. Engler, Katherine E. Huang, XinRen, Yanli Wang, Xin Bernstein, John T. Li, Kamran Atabai, Xiaozhu Huang, Dean34

Sandler Asthma Basic REsearch CenterCore FacilitiesSheppard. IL-17A produced by ab T cells drives airway hyper-responsiveness in miceand enhances mouse and human airway smooth muscle contraction. Nature Medicine.2012 March 4;18(4)547-545. Thornton E, Looney M, Sheppard D, Locksley R, Huang X, Krummel M. Dynamics ofantigen capture and presentation revealed by two-photon live imaging in the lung. J ExpMed. 2012 Jun 4;209(6):1183-996. Schroeder BW, Verhaeghe C, Park SW, Nguyenvu LT, Huang X, Zhen G, Erle DJ.AGR2 is Induced in Asthma and Promotes Allergen-Induced Mucin Overproduction. AmJ Respir Cell Mol Biol. 2012 Aug;47(2):178-857. Bhattacharya M, Su G, Su X, Oses-Prieto JA, Li JT, Huang X, Hernandez H, Atakilit A,Burlingame AL, Matthay MA, Sheppard D. IQGAP1 is necessary for pulmonary vascularbarrier protection in murine acute lung injury and pneumonia. Am J Physiol Lung CellMol Physiol. 2012 Jul 1;303(1):L12-98. Chun Chen, Makoto Kudo, Florentine Rutaganira, Hiromi Takano, Candace Lee, AmhaAtakilit, Toshimitsu Uede, Paul Wolters, Stephen Liggett, Kevan M. Shokat, XiaozhuHuang and Dean Sheppard . Integrin α9β1 in airway smooth muscle regulates a novelbrake on exaggerated murine and human airway narrowing. JCI 2012 2012 Aug1;122(8):2916-279. Huang F, Zhang H, Wu M, Yang H, Kudo M, Peters CJ, Woodruff PG, Solberg OD,Donne ML, Huang X, Sheppard, Fahy JV, Wolters PJ, Hogan BL, Finkbeiner WE, Li M,Jan YN, Jan LY, Rock JR. Calcium-activated chloride channel TMEM16A modulatesmucin secretion and airway smooth muscle contraction. Proc Natl Acad Sci U S A. 2012Oct 2;109(40):16354-9.10. Julia Freimuth, Frederic F. Clermont, Xiaozhu Huang, Angela De Sapio, TakuTokuyasu, Dean Sheppard, Rosemary J. Akhurst. Epistatic interactions between Tgfb1and genetic loci, Tgfbm2 and Tgfbm3, determine susceptibility to an asthmatic stimulus.Proc Natl Acad Sci U S A. 2012 Oct 30;109(44):18035

Sandler Asthma Basic Research CenterCore FacilitiesFunctional Genomics CoreDirector: David J. Erle, M.D.Associate Director: Andrea BarczakObjectiveTo make cutting-edge functional genomics technology readily available for investigatorsresearching questions relevant to basic biology of asthma.AccomplishmentsSupported projects: We continue to support many investigators studying immunology, airwaycell biology, lung development, and other relevant areas. This includes faculty members whoparticipate actively in a range of SABRE activities (including Ansel, Chapman, Erle, Krummel,Seaman, Sheppard, and Woodruff) and AAF-funded investigators (Keoki Williams and DanielConrad). Here is a partial listing of relevant projects that have been completed this year or arestill in progress:PIMark AnselMark AnselMark AnselHarold ChapmanHarold ChapmanDavid ErleDavid ErleDaniel Conrad 1 *Matthew KrummelMehrdad MatloubianJason RockWilliam SeamanDean SheppardProject (status)Effect of Eri1 on mRNA profile and translation in natural killercells. Completed.The miR-17~92 cluster regulates TFH cell differentiation.Completed.Empirical determination of miRNA targets with comparativeRNA-Seq and PAR-CLIP. In Progress.Beta4 positive AECs vs. B4 negative AECs. Completed.Ephb2/B4 progenitor isolation. Completed.IL-13 and IL-17 responsive microRNAs in the airwayepithelium. Completed.RNA-Seq analysis of IL-13 treated airway epithelium.Completed.The Kainic Acid Receptor-ADAM10 Axis in Asthma. InProgress.Chemotactic circuits in a mouse tumor model. Completed.Plasmacytoid Dendritic Cell Response to a Viral InfectionCompleted.Gene expression differences between WT and MMP3 KO afterpneumonectomy. In Progress.Microglia expression profile after TBI. Completed.RNA-Seq analysis of the role of integrin alpha-v in lung andliver fibrosis. In Progress.36

Sandler Asthma Basic Research CenterCore FacilitiesKeoki Williams 2 *Asa Wheelock 3Prescott WoodruffPharmacogenomics of asthma. Ongoing.COPD and Gender (COSMIC). Completed.miRNA profiling in asthma patients. Ongoing.1 Virginia Commonwealth University, 2 Henry Ford Health,3 Karolinska Institutet, *AAF awardeePersonnelAndrea Barczak (manager), Rebecca Barbeau (SRA), and Joshua Pollack (biostatistician)continue to provide outstanding service to core users. In aggregate, they have over 20 years ofexperience as core staff.New technologiesThe SABRE functional genomics core is a resource for the UCSF community (and beyond); wecollaborate on more than 65 projects per year. SABRE support is critical for development andimplementation of new methods. Priority is given to development of methods required forstudies requested by SABRE investigators. Although microarrays continue to be a very usefuland cost effective method for genome-wide profiling of mRNAs and miRNAs, recent advancesin sequencing technology offer substantial advantages over arrays for most global mRNA andmiRNA profiling projects. RNA-Seq has superior sensitivity, specificity and reproducibility;offers the potential for novel RNA discovery (especially important for non-coding RNAs); andcan be used for analyzing transcript variation (alternative splicing and polyadenylation, allelespecificexpression). Supply costs for RNA-Seq continue to drop and are now roughly similar tocosts for array experiments. Over the past two years, an increasing number of users haveswitched to RNA-Seq technologies. We have seen a rise from 2 projects in 2011 to 13 projects in2012 and anticipate that this trend will continue to grow at a rapid rate. This past year, we havefocused the majority of our efforts on implementing the following next generation sequencingservices: 1) methods for analysis of partially degraded or FFPE RNA, 2) improving samplethroughput for small RNA-Seq and 3) continued development of state-of-the-art methods foranalyzing next generation sequencing data.1) RNA-Seq analysis of degraded RNA: Standard mRNA-Seq library construction methodscontain an initial poly(A) RNA selection to remove highly abundant rRNA species beforeamplification; this method presents a challenge for clinical samples where degradation can be acommon problem. We have employed an alternative non-poly(A) based ribosomal depletionmethod (Ribo-Zero, Epicentre, Inc.) to accommodate samples that have compromised RNAintegrity. An additional benefit of this technology is that it recovers the 5’and 3’ ends of bothmRNAs and long non-coding RNAs. This is an attractive alternative to standard protocols forinvestigators who are interested novel gene discovery and expression of lncRNAs. We arecurrently analyzing data from our first set of ribosomal depleted samples.2) Improving sample throughput for small RNA-Seq: miRNA expression profiling accountsto approximately 20% of the projects that we process, including studies with Mark Ansel andPrescott Woodruff who are working on determining the miRNA expression patterns that areassociated with asthma pathology and response to therapy. Small RNA-Seq library preparation37

Sandler Asthma Basic Research CenterCore Facilitiesprotocols require a gel purification based size selection step for each sample library. This processis laborious, time consuming, and not amenable to higher-throughput methods. We haveimplemented a newer library preparation method that allows us to multiplex libraries before gelpurification, which cuts down the turn-around time substantially. Additionally, the ability tomultiplex small RNA-Seq libraries significantly decreases the associated costs for the samplepreparation and sequencing by up to as much as 50%. To date, we have processed over 24samples using this new method.3) Development of data analysis pipelines: RNA-Seq data analysis presents many newchallenges including alignment of millions of reads to a reference transcriptome (or genome),assembly of read alignments, and development of new algorithms for normalization andstatistical analysis of differential expression. Different tools are required to carry out each step ofthe analysis and the size and complexity of the datasets make the process computationallyexpensive and time consuming. This past year our biostatistician, Josh Pollack, has madesignificant progress towards developing pipelines that incorporate state-of-the-art algorithmsfrom publicly available software, thereby streamlining the process and decreasing the turnaroundtime. We have implemented these new pipelines, and have analyzed data from bothmRNA and miRNA studies. NGS data analysis requires substantial processing power and it wasessential for us to acquire a new computer. SABRE funding contributed to the purchase of a 12-core workstation with 96 GB of RAM and 6TB of disk storage.Plans for the coming yearWe have optimized protocols for library generation and other steps in the process and now offercomprehensive RNA-Seq services (including library preparation, coordination of sequencingruns, and data analysis), which relieves investigators of the need to develop and optimizeprotocols in their own laboratories. We have begun a new initiative to reduce turnaround time forRNA-Seq projects. SABRE support allows us to provide a substantial discount to SABREinvestigators and in recognition of this support SABRE projects receive higher priority than non-SABRE projects.We will continue to offer assistance with whole-genome analysis of mRNA and miRNAexpression and ChIP analysis. In addition to the array-based analyses offered in previous years,we are encouraging investigators to employ next generation sequencing-based approaches(RNA-Seq, small RNA-Seq, and ChIP-Seq) where appropriate. Further work is planned toimplement protocols that will allow the following: 1) analysis of very limited amounts of startingmaterial (starting with as little as 5 ng of total RNA), 2) strand-specific library preparation foranalysis of non-coding RNAs and antisense transcription and improved annotation of novelgenes, and 3) ChIP-Seq library preparation and analysis. We will also continue to implementstate-of-the-art methods for analyzing next generation sequencing data. Short-term goals includethe development of pipelines for the following: 1) analysis of differential isoform expression, 2)analysis of non-coding RNAs and 3) implementation of visualization tools to display nextgenerationsequencing data more effectively.Training and Integration with SABRE and AAF programsWe provide extensive consultation and training for investigators using the core. We meet witheach group (PI and other group members, including students and postdoctoral fellows) to help38

Sandler Asthma Basic Research CenterCore Facilitieswith project planning. We help with grant preparation, sample size determination, appropriateselection of controls, and RNA extraction protocols. We meet with each group again after theinitial data analysis to discuss the results and provide guidance about further analysis. Whenwork is being readied for publication, we assist with preparation of figures and tables andsubmission of the results to a public database (NCBI’s Gene Expression Omnibus [GEO]). Thecore director attends the monthly UCSF SABRE Research Conference and the annual AAFmeeting. This allows many opportunities for raising awareness about the core services amongSABRE and AAF investigators. Although we continue to work with other investigators in orderto maintain the high volume needed to operate in an economical manner, SABRE projectsreceive the highest priority.In late 2012, David Erle (contact PI) and Esteban Burchard (co-PI) submitted a K12 proposal inresponse to an NIH RFA for “Career Development Programs in Omics of Lung Diseases.” 30UCSF faculty members with expertise in genomics (and other “omics”) and in asthma and otherlung diseases agreed to participate. If successful, this proposal will provide salary support for 2junior faculty K scholars per year to receive training in applying omics technologies to lungdiseases.Grants and PublicationsGrantsThe core is now supported by SABRE and by a recharge mechanism, which covers labor andreagent costs for projects performed by the core. Core staff members work closely withinvestigators as they apply for NIH funding via R01 and other mechanisms. The following listincludes asthma-related projects supported by the core that received new NIH funding during thelast year and projects now applying for additional funding from NIH:PI Project Number TitleAnsel, Karl Mark 1R01HL109102-01 Role of miRNAs In Th2-drivenInflammation in AsthmaChapman, Harold A 1U01HL111054-01Epithelial Progenitor Cells in LungRepair and RegenerationGerber, Anthony N 1R01 HL109557-01A1 Role of Klf15 in Airway Smooth Muscleand the Response to GlucocorticoidsPending:Sheppard, Dean 5U19AI077439 Mechanisms of Initiation and Persistenceof Allergic Asthma(funding expected based on impact score of 20 and assurances from NIH program official)Frank, James A R21 HL111707-01A1 A Claudin-18 Deficiency in thePathogenesis of AsthmaErle, David J and Burchard, E (multi-PI)UCSF Career Development Program in39

Sandler Asthma Basic Research CenterCore Facilities1K12HL119997-01 Omics of Lung DiseasesArjomandi, Mehrdad VA I21 Respiratory Tract Immune System in Gulf War IllnessPlanned for submission in early 2013:Rock, Jason AAF Tmem16a as a modulator of airway mucin dynamicsRock, Jason NIH (R21) Requirement for spontaneous contractions of the embryonicairway smooth muscle during lung developmentKeoki Williams NIH (R01) Combined transcriptomics and genomics to find asthmagenes in admixed populations(the core has a subcontract to perform RNA-Seq for roughly 800 samples on this grant proposal)The UCSF Clinical and Translational Sciences Institute provided some core funding until July2011, when CTSI elected not to continue to support any core laboratories. This reduced our nonrechargefunding. Hence continued support from SABRE is critical in allowing us to maintainservices and develop new technologies for support of SABRE investigators.PublicationsCore-supported projects led by SABRE-affiliated faculty:1. Bronevetsky Y, Villarino A, Eisley C, Barbeau R, Barczak AJ, Tarakhovsky A, Erle DJ,Rao A, Ansel KM. T cell activation induces proteasomal degradation of Argonaute andrapid remodeling of the microRNA repertoire. J Exp Med. In press.2. Diez D, Goto S, Fahy JV, Erle DJ, Woodruff PG, Wheelock ÅM, Wheelock CE.Network analysis identifies a putative role for the PPAR and type 1 interferon pathwaysin glucocorticoid actions in asthmatics. BMC Med Genomics. 2012 Jun 19;5:27.3. Levänen B, Bhakta NR, Paredes PT, Barbeau R, Hiltbrunner S, Pollack JL, Sköld CM,Svartengren, Grunewald J, Gabrielsson S, Eklund A, Larsson, Woodruff PG, David J ErleDJ, Wheelock AM. Altered MicroRNA profiles in Bronchoalveolar Lavage FluidExosomes in Asthma J Allergy Clin Immunol. In press.4. Seumois G, Vijayanand P, Eisley CJ, Omran N, Kalinke L, North M, Ganesan AP,Simpson LJ, Hunkapiller N, Moltzahn F, Woodruff PG, Fahy JV, Erle DJ, Djukanovic R,Blelloch R, Ansel KM. An Integrated nano-scale approach to profile miRNAs in limitedclinical samples. Am J Clin Exp Immunol. 2012 Nov 30;1(2):70-89.5. Solberg OD, Ostrin EJ, Love MI, Peng JC, Bhakta NR, Hou L, Nguyen C, Solon M,Nguyen C, Barczak AJ, Zlock LT, Blagev DP, Finkbeiner WE, Ansel KM, Arron JR,Erle DJ, Woodruff PG. Airway epithelial miRNA expression is altered in asthma. Am JRespir Crit Care Med. 2012 Nov 15;186(10):965-74.6. Sugimoto K, Kudo M, Sundaram A, Ren X, Huang K, Bernstein X, Wang Y, RaymondWW, Erle DJ, Abrink M, Caughey GH, Huang X, Sheppard D. The αvβ6 integrinmodulates airway hyperresponsiveness in mice by regulating intraepithelial mast cells. JClin Invest. 2012 Feb 1;122(2):748-58.40

Sandler Asthma Basic Research CenterCore Facilities7. Thomas MF, Abdul-Wajid S, Panduro M, Babiarz JE, Rajaram M, Woodruff P, LanierLL, Heissmeyer V, Ansel KM. Eri1 regulates microRNA homeostasis and mouselymphocyte development and antiviral function. Blood. 2012 Jul 5;120(1):130-42.Under review:Hsieh CL, Kim CC, Ryba BE, Niemi EC, Locksley RM, Liu J, Nakamura MC, Seaman WE.Traumatic brain injury induces unique macrophage subsets. Submitted.Sasse SK, Mailloux CM, Barczak AJ, Wang Q, Jain MK, Haldar SM, Gerber AN. GR and Klf15regulate gene expression dynamics and integrate signals through feed forward circuitry. Inrevision.Zhao W, Pollack JL, Blagev D, Erle DJ. Massively parallel mapping of 3’ UTR cis-regulatoryelements controlling mRNA stability. Submitted.Other core-supported projects:Broadhurst MJ, Ardeshir A, Kanwar B, Mirpuri J, Gundra UM, Leung JM, Wiens KE, Vujkovic-Cvijin I, Kim CC, Yarovinsky F, Lerche NW, McCune JM, Loke P. Therapeutic helminthinfection of macaques with idiopathic chronic diarrhea alters the inflammatory signature andmucosal microbiota of the colon. PLoS Pathog. 2012 Nov;8(11):e1003000.Petrillo LA, Wolf DM, Kapoun AM, Wang NJ, Barczak A, Xiao Y, Korkaya H, Baehner F,Lewicki J, Wicha M, Park JW, Spellman PT, Gray JW, van't Veer L, Esserman LJ. Xenograftsfaithfully recapitulate breast cancer-specific expression patters of parent primary breast tumors.Breast Cancer Res Treat. 2012 Oct;135(3):913-22.Under review:So AY, Garcia-Flores Y, Minisandram A, Martin A, Taganov K, Boldin M, Baltimore D.Regulation of APC development, immune response, and autoimmunity by Bach1/HO-1 pathwayin mice. Blood 2012 Sep 20;120(12):2428-37.Baraban SC, Dinday MT, Hortopan GA. Drug screening for Dravet syndrome using Scn1azebrafish mutants. Submitted.Hortopan GA and Baraban SC. Morpholino-based knockdown of LIS1 in zebrafish larvae:analysis of seizure activity and differential gene expression using microarrays. Submitted41

Sandler Asthma Basic Research CenterCore FacilitiesGenetics CoreDirector: Esteban González Burchard, M.D., M.P.H.,Professor of Bioengineering & Therapeutic Sciences and MedicineVision: We built a multidisciplinary research center and we are taking a comprehensiveapproach to asthma research. Our approach integrates gene-environment studies with basicbiology, population genetics, social and environmental epidemiology. We built a network of“minority serving” providers to recruit well-phenotyped subjects from throughout the U.S. andPuerto Rico. As a result of our efforts we have assembled the largest gene-environment studypopulation of minority children with and without asthma in the U.S. (total sample n = 9,144).Finally, we have recruited two new faculty, Dara Torgerson, Ph.D. and Noah Zaitlen, Ph.D. intothe Lung Biology Center. Both scientists are up and coming leaders in their respective fields(described below).We have established the Asthma Genetics Core Facility to facilitate asthma genetic researchamong Sandler/AAF-sponsored investigators. In keeping with the Mission of the originalSandler-sponsored Asthma Research Program, we have made this resource “Open Source” byhaving an extensive range of national and international collaborations. We offer investigators a“full service of genetic testing and analyses.” Specifically, we analyze promising candidate genesidentified by investigators using biologic material (DNA and plasma) from large wellphenotypedfamily-based and case-control asthma studies of racially/ethnically diverse subjects.This past year the Genetics Core Facility has focused on three main goals: 1) collaboration 2)well-phenotyped patient recruitment of Latino and African American subjects with and withoutasthma and 3) faculty recruitment.Accomplishments in 2012:1) Collaboration:a) UCSF Sandler Program and the AAF: In the era of large “Team Science” the value andimportance of collaboration cannot be overstated. We have made the existing cohortswidely available to Sandler sponsored investigators (UCSF Sandler Program and theAAF). The Asthma Genetics Core assists investigators with study design and providesgenotyping and expertise with statistical genetic analyses. We also allow our data to beused for replication of promising results from other investigative groups.b) Collaborating Faculty: In 2012 we have collaborated with the following faculty: RyanHernandez (UCSF), Carol Ober (Chicago), Kathleen Barnes (John’s Hopkins), EvanEicher (University of Washington), Jim Gauderman (USC), Charles Rotimi(NIH/NHGRI), Noah Zaitlen (UCSF), Mario Castro (Washington University), L. KeokiWilliams (Henry Ford), Fernando Martinez (University of Arizona), Max Seibold(National Jewish), Neil Trivedi (UCSF), Rajesh Kumar (Children’s Memorial Hospital,Chicago), Pedro Avila (Northwestern University), Stephanie London (NIEHS), ScottWeiss (Harvard), and Kathy Giacomini (UCSF). We have contributed our data to nationaland international consortiums to study asthma, obesity and eczema.42

Sandler Asthma Basic Research CenterCore Facilitiesc) We have generated genome wide association studies (GWAS) data from our studypopulations and provided our results as in silico replication to supplement initial findingsfor several Sandler investigators. In addition, we have worked closely with asthmainvestigators throughout the country to advance the field by collectively working towardstesting and replicating novel genetic associations identified from basic science models(animal and human) to GWAS.d) EVE Asthma Consortium: This past year we participated in the NHLBI-sponsored EVEAsthma Consortium, which was published in Nature Genetics. The lead author, DaraTorgerson, was recently recruited to UCSF as an Assistant Professor in the Lung BiologyCenter.Admixture Mapping Meta-analysis in EVE: Through our work with the EVEConsortium we are currently working on a follow-up to the original GWAS to findadditional loci via ancestry association or admixture mapping. We have combined datafrom the African-American and Hispanic/Latino studies within EVE (9 studies in total),comprising over 7,000 individuals. For all individuals we have estimated local ancestryusing LAMP algorithms to have locus-specific ancestry calls for all individuals across thegenome. The studies comprise a diverse group of designs including case-control, triobased,and pedigrees. Within this project we have developed novel ancestry imputationmethods as well as methods for admixture mapping on large datasets. For replication wehave leveraged our study, GALA II, as it is the largest study of asthma with genome-widedata in U.S. minority pediatric populations. We identified SMAD2 as a novel risk factorfor asthma in Latino populations. Our results were supported by differential geneexpression between children with and without asthma. We did not find the sameassociation in African or European Americans. The manuscript has been approved by allco-authors and will be submitted to Nature Genetics by January 2013.e) Genentech (Joe Aaron): We have entered into a collaboration with Genentech to test theability to use biomarkers (periostin) and clinical phenotypes to stratify children withasthma into high and low drug responders to Genentech’s new anti-IL13 therapy(Lebrikizumab).f) Gene expression: We are collaborating with Mario Castro (Washington University) andMax Seibold (National Jewish Health Center) to compare gene expression in lungtissue/lavage vs. nasal epithelia vs. peripheral blood. We hypothesize that nasal epithelialtissue gene expression will be a good proxy for gene expression in the lung. If ourhypothesis is correct, it will facilitate large scale sampling of nasal epithelial tissue fromhundreds of children with and without asthma.2) Patient Recruitment: We recruited three study populations: 1) the Genetics of Asthma inLatino Americans (GALA I) Study (parent-child trios), a family-based study of Puerto Ricanand Mexican children with asthma 2) the Genes-environments & Admixture in LatinoAsthmatics (GALA II) Study, a case-control study at 5 urban centers across the U.S. and 3)the Study of African Americans Asthma, Genes & Environments (SAGE), a case-controlstudy in the San Francisco Bay Area. Combined we now have the largest pediatric asthma43

Sandler Asthma Basic Research CenterCore Facilitiesgenetic study of Latino and African American pediatric populations in the U.S. (n > 9,144children with and without asthma). We are continuing to recruit and better characterizechildren with and without asthma.In collaboration with Genentech we are performing a longitudinal study of asthma treatmentand control in a subset of the study population (n~1000). All subjects are extensively wellphenotyped. We have detailed clinical measurements (spirometry, maximal bronchodilatorresponse testing, methacholine challenge, skin prick testing, and IgE measurements, exhalednitric oxide, skin color reflectance), biologic specimens (serum, RNA, DNA and nasalepithelia), geocoded air pollution measures and questionnaire-based information regardingenvironmental and social risk factors. We have genome-wide data available for all GALA Iand II participants. We will combine biomarkers and sub-phenotypes to identify high and lowdrug responders to anti-IL13 therapy.3) Faculty Recruitment: We have recruited two young scientists, who have significantresearch experience in minority populations and asthma genetics. Dara Torgerson, Ph.D. led thelargest genomewide meta-analysis of asthma in the U.S., which was published in NatureGenetics. She trained with Drs. Carole Ober and Dan Nicolae of the University of Chicago. Wealso recruited Dr. Noah Zaitlen from the Harvard University School of Public Health. Hisexpertise is gene-environment interactions and he will apply his theoretical methods to studyasthma in minority populations.Financial Support:We have been successful at leveraging Sandler funding with NIH and industry support. Theaforementioned efforts are supported by the equivalent of four NIH RO1 grants.Active Grants:1. 1R01 HL104608-01A1: subcontract ~ $400,000, September 28, 2011-June 30, 2015, PI:Barnes2. 1P60 MD006902: ~$1 million, August 27, 2012-February 28, 2017. PI, Bibbins-Domingo. Project PI: Burchard.Grants under review:1. K24 - Epigenomics of tobacco exposure on asthma severity among minority children2. RO1 – Sequencing Candidate Genes Under Admixture Mapping Peaks in LatinoAsthmatics. Under review.3. RO1 - Pharmacogenomics of Bronchodilator Response in Minority Children withAsthma. Scored in the 9 th percentile. Pending council review.44

Sandler Asthma Basic Research CenterCore FacilitiesPublications supported by the Strategic Program for Asthma Research and/or the SandlerFamily Foundation.2012 Publications1. Fejerman, L., Chen, G.K., Eng, C., Huntsman, S., Hu, D., Williams, A., Pasaniuc, B.,John, E.M., Via, M., Gignoux, C., Ingles, S., Monroe, K.R., Kolonel, L.N., Torres-Mejía,G., Pérez-Stable, E.J., González Burchard E., Henderson, B.E., Haiman, C.A., Ziv E.(2012) Admixture mapping identifies a locus on 6q25 associated with breast cancer riskin US Latinas. Hum Mol Genet. 2012 Jan 19.2. Kumar R, Tsai HJ, Hong X, Gignoux C, Pearson C, Ortiz K, Fu M, Pongracic JA,Burchard EG, Bauchner H, Wang X. African ancestry, early life exposures, andrespiratory morbidity in early childhood. Clin Exp Allergy. 2012 Feb;42(2):265-74. doi:10.1111/j.1365-2222.2011.03873.x. Epub 2011 Sep 25. PMID: 220930773. Xu H, Cheng C, Devidas M, Pei D, Fan Y, Yang W, Neale G, Scheet P, Burchard EG,Torgerson DG, Eng C, Dean M, Antillon F, Winick NJ, Martin PL, Willman CL, CamittaBM, Reaman GH, Carroll WL, Loh M, Evans WE, Pui CH, Hunger SP, Relling MV,Yang JJ. ARID5B genetic polymorphisms contribute to racial disparities in the incidenceand treatment outcome of childhood acute lymphoblastic leukemia. J Clin Oncol. 2012Mar 1;30(7):751-7. Epub 2012 Jan 30. PMID: 222910824. Galanter, J.M., Fernandez, J.C., Gignoux, C.R., Barnholtz-Sloan, J., Fernandez, C., Via,M., Hidalgo-Miranda, A., Contreras, A.V., Uribe Figueroa, L., Raska, P., Jimenez-Sanchez, G., Silva Zolezzi, I., Torres, M., Ruiz Ponte, C., Ruiz, Y., Salas, A., Nguyen, E.,Eng, C., Borjas, L., Zabala, W., Barreto, G., Rondón, F., Ibarra, A., Taboada, P., Porras,L., Moreno, F., Bigham,A., Gutierrez, G., Brutsaert, T., León-Velarde, F., Moore, L.G.,Vargas, E., Cruz, M., Escobedo, J., Rodriguez-Santana, J., Rodriguez-Cintrón, W.,Chapela, R., Ford, J.G., Bustamante, C.D., Seminara, D., Shriver, M.D., Ziv, E.,Burchard, E.G., Haile, R., Parra, E., Carracedo, A. for the Latin American CancerEpidemiology (LACE) Consortium. Development of a Panel of Genome-wide AncestryInformative Markers to Study Admixture Throughout the Americas. PLoS Genet. 2012Mar;8(3):e1002554. Epub 2012 Mar 8. PMID: 224123865. Avena S, Via M, Ziv E, Pérez-Stable EJ, Gignoux CR, Dejean C, Huntsman S, Torres-Mejía G, Dutil J, Matta JL, Beckman K, Burchard EG, Parolin ML, Goicoechea A,Acreche N, Boquet M, Ríos Part Mdel C, Fernández V, Rey J, Stern MC, Carnese RF,Fejerman L. Heterogeneity in genetic admixture across different regions of Argentina.PLoS One. 2012;7(4):e34695. 2012 Apr 10. PMID: 225060446. Fejerman L, Chen GK, Eng C, Huntsman S, Hu D, Williams A, Pasaniuc B, John EM,Via M, Gignoux C, Ingles S, Monroe KR, Kolonel LN, Torres-Mejía G, Pérez-Stable EJ,Burchard EG, Henderson BE, Haiman CA, Ziv E. Admixture mapping identifies a locuson 6q25 associated with breast cancer risk in US Latinas. Hum Mol Genet. 2012 Apr15;21(8):1907-17. Epub 2012 Jan 6. PMID: 222280987. Kenny EE, Timpson NJ, Sikora M, Yee MC, Moreno-Estrada A, Eng C, Huntsman S,45

Sandler Asthma Basic Research CenterCore FacilitiesBurchard EG, Stoneking M, Bustamante CD, Myles S. Melanesian blond hair is causedby an amino acid change in TYRP1. Science. 2012 May 4;336(6081):554. PMID:225562448. Baran Y, Pasaniuc B, Sankararaman S, Torgerson DG, Gignoux C, Eng C, Rodriguez-Cintron W, Chapela R, Ford JG, Avila PC, Rodriguez-Santana J, Burchard EG,Halperin E. Fast and accurate inference of local ancestry in Latino populations.Bioinformatics. 2012 May 15;28(10):1359-67. Epub 2012 Apr 11. PMID: 224957539. Torgerson DG, Capurso D, Ampleford EJ, Li X, Moore WC, Gignoux CR, Hu D, Eng C,Mathias RA, Busse WW, Castro M, Erzurum SC, Fitzpatrick AM, Gaston B, Israel E,Jarjour NN, Teague WG, Wenzel SE, Rodríguez-Santana JR, Rodríguez-Cintrón W,Avila PC, Ford JG, Barnes KC, Burchard EG, Howard TD, Bleecker ER, Meyers DA,Cox NJ, Ober C, Nicolae DL. Genome-wide ancestry association testing identifies acommon European variant on 6q14.1 as a risk factor for asthma in African Americansubjects. J Allergy Clin Immunol. 2012 May 17. PMID: 2260799210. Oh SS, Tcheurekdjian H, Roth LA, Nguyen EA, Sen S, Galanter JM, Davis A, Farber HJ,Gilliland FD, Kumar R, Avila PC, Brigino-Buenaventura E, Chapela R, Ford JG, LeNoirMA, Lurmann F, Meade K, Serebrisky D, Thyne S, Rodriguez-Cintron W, Rodriguez-Santana JR, Williams LK, Borrell LN, Burchard EG. Effect of secondhand smoke onasthma control among black and Latino children. J Allergy Clin Immunol (2012). 2012Jun;129(6):1478-83.e7. Epub 2012 Apr 30. PMID: 2255210911. Aldrich MC, Kumar R, Colangelo LA, Williams LK, Sen S, Kritchevsky SB, MeibohmB, Galanter J, Hu D, Gignoux CR, Liu Y, Harris TB, Ziv E, Zmuda J, Garcia M, LeakTS, Foreman MG, Smith LJ, Fornage M, Liu K, Burchard EG; for the Health ABC andCARDIA Studies. Genetic Ancestry-Smoking Interactions and Lung Function in AfricanAmericans: A Cohort Study. PLoS One. 2012 June;7(6):e39541. Epub 2012 Jun 21.PMID: 2273724412. Aminuddin F, Akhabir L, Stefanowicz D, Paré PD, Connett JE, Anthonisen NR, Fahy JV,Seibold MA, Burchard EG, Eng C, Gulsvik A, Bakke P, Cho MH, Litonjua A, LomasDA, Anderson WH, Beaty TH, Crapo JD, Silverman EK, Sandford AJ. Geneticassociation between human chitinases and lung function in COPD. Hum Genet. 2012Jul;131(7):1105-14. Epub 2011 Dec 28. PMID: 2220076713. Torgerson, DG, Gignoux, CR, Galanter, JM, Drake, KA, Roth, LA, Eng C, Huntsman, S,Torres, R, Avila, PC, Chapela, R, Ford, JG, Rodríguez-Santana, JR, Rodríguez-Cintrón,W, Hernandez, RD, and Burchard, EG. Case-control admixture mapping in Latinopopulations enriches for known asthma-associated genes. Journal of Asthma and ClinicalImmunology. J Allergy Clin Immunol. 2012 Jul;130(1):76-82.e12. Epub 2012 Apr 13.PMID: 2250279714. Nguyen EA, Burchard EG. Asthma Research for All of the United States. PediatrAllergy Immunol Pulmonol. 2012 Sep;25(3):128-131. PMID: 2297042246

Sandler Asthma Basic Research CenterCore Facilities15. Kumar R, Williams LK, Kato A, Peterson EL, Favoreto S Jr, Hulse K, Wang D,Beckman K, Thyne S, Lenoir M, Meade K, Lanfear DE, Levin AM, Favro D, Yang JJ,Weiss K, Boushey HA, Grammer L, Avila PC, Burchard EG, Schleimer R. Geneticvariation in B cell-activating factor of the TNF family (BAFF) and asthma exacerbationsamong African American subjects. J Allergy Clin Immunol. 2012 Oct. Epub 2012 June.PMID: 2272808016. Myers RA, Himes BE, Gignoux CR, Yang JJ, Gauderman WJ, Rebordosa C, XieJ, Torgerson DG, Levin AM, Baurley J, Graves PE, Mathias RA, Romieu I, RothLA, Conti D, Avila L, Eng C, Vora H, Lenoir MA, Soto-Quiros M, Liu J, CeledónJC, Farber HJ, Kumar R, Avila PC, Meade K, Serebrisky D, Thyne S, Rodriguez-CintronW, Rodriguez-Santana JR, Borrell LN, Lemanske RF Jr, Bleecker ER, MeyersDA, London SJ, Barnes KC, Raby BA, Martinez FD, Gilliland FD, WilliamsLK, Burchard EG, Weiss ST, Nicolae DL, Ober C. Further replication studies of theEVE Consortium meta-analysis identifies 2 asthma risk loci in European Americans. JAllergy Clin Immunol. 2012 Dec;130(6):1294-301. doi: 10.1016/j.jaci.2012.07.054. Epub2012 Oct 4.17. Levin AM, Mathias RA, Huang L, Roth LA, Daley D, Myers RA, Himes BE, RomieuI, Yang M, Eng C, Park JE, Zoratti K, Gignoux CR, Torgerson DG, GalanterJM,Huntsman S, Nguyen EA, Becker AB, Chan-Yeung M, Kozyrskyj AL, KwokPY, Gilliland FD, Gauderman WJ, Bleecker ER, Raby BA, Meyers DA, LondonSJ,Martinez FD, Weiss ST, Burchard EG, Nicolae DL, Ober C, Barnes KC, WilliamsLK. A meta-analysis of genome-wide association studies for serum total IgE in diversestudy populations. J Allergy Clin Immunol. 2012 Nov 10. doi:10.1016/j.jaci.2012.10.002. 2012 Nov [Epub ahead of print]Manuscripts currently under review:1. Rajesh Kumar, Elizabeth A Nguyen, Lindsey A Roth, Sam S Oh,Christopher R Gignoux,Scott Huntsman, Celeste Eng, Andres Moreno-Estrada, Karla Sandoval, RosendaPeñaloza-Espinosa, Marisol López-López, Pedro C Avila, Harold J Farber, HaigTcheurekdjian, William Rodriguez-Cintron, Jose R Rodriguez-Santana, DeniseSerebrisky, Shannon M Thyne, Keoki Williams, William Klitz, Cheryl Winkler, Carlos DBustamante, Eliseo J Pérez-Stable, Luisa N Borrell, Esteban G Burchard. Factorsassociated with degree of atopy in Latino children in a nationwide pediatric sample: TheGALA II Study. J Allergy Clin Immunol. (Under 2 nd review, December 2013).2. Joshua M Galanter, Christopher R Gignoux, Dara G Torgerson, Lindsey A Roth, CelesteEng, Sam S Oh, Elizabeth A Nguyen Scott Huntsman Donglei Hu, Saunak Sen. AdamDavis, Harold J. Farber, Pedro C. Avila, Emerita Brigino-Buenaventura, Michael A.LeNoir, Kelley Meade, Denise Serebrisky, Stephanie London, Frank Gilliland, FernandoMartinez, Luisa N Borrell, William Rodriguez-Cintron, Rajesh Kumar, Jose R.Rodriguez-Santana, Esteban G. Burchard, and the EVE Consortium. Genome-wideassociation and admixture mapping identify chromosomal regions 17q21 and 6p21 asasthma-associated loci in Latinos. AJRCCM. (Under review December 2013).47

Sandler Asthma Basic Research CenterCore Facilities3. Luisa N. Borrell, Elizabeth A. Nguyen, Lindsey A. Roth,Sam S. Oh, HaigTcheurekdjian,Saunak Sen, Adam Davis, Harold J. Farber, Pedro C. Avila, EmeritaBrigino-Buenaventura, Michael A. LeNoir, Fred Lurmann, Kelley Meade, DeniseSerebrisky, William Rodriguez-Cintron, Rajesh Kumar, Jose R. Rodriguez-Santana,Shannon Thyne, Esteban G. Burchard. Childhood obesity and asthma control in adiverse sample: Examining age and racial/ethnic differences. AJRCCM. (Submitted for2nd review January 2013).4. Chris R Gignoux, Dara G Torgerson, Joshua Galanter, Lindsey A Roth, Celeste Eng,Elizabeth A Nguyen, Scott Huntsman, Sam S Oh,Raskia A Mathias, Adam Davis, HaroldJ Farber, Pedro C Avila, Emerita Brigino-Buenaventura, Michael A LeNoir, KelleyMeade, Denise Serebrisky, Luisa N Borrell, William Rodriguez-Cintron, Rajesh Kumar,Jose R Rodriguez-Santana, Andres Moreno, Karla Sandoval, Cheryl Winkler, CarlosBustamante, EVE Collaborators, Carole Ober, Dan Nicholae, Saunak Sen, Kathleen CBarnes, Esteban G Burchard. Meta-analysis of admixture mapping using existinggenome-wide association data implicates SMAD2 as a novel asthma-associated locus inLatinos. Nature Genetics. (Submitted January 2013).5. Katherine A. Drake, Dara G. Torgerson, Christopher R. Gignoux, Joshua M. Galanter,Lindsey A. Roth, Scott Huntsman, Celeste Eng, Sam S. Oh, Sook Wah Yee, LawrenceLin, Adam Davis, Luisa N. Borrell, Harold J. Farber, Rajesh Kumar, Pedro C. Avila,Emerita Brigino-Buenaventura, Rocio Chapela, Jean G. Ford, Michael A. LeNoir, FredLurmann, MS, Kelley Meade, Denise Serebrisky, Shannon Thyne, William Rodríguez-Cintrón, Saunak Sen, José R. Rodríguez-Santana, Kathleen M. Giacomini, and EstebanG. Burchard. A Genome-wide Association Study of Bronchodilator Response inLatinos Implicates Rare Variants. J Allergy Clin Immunol. (Submitted January 2013).6. Katherine K. Nishimura, Joshua M. Galanter, Lindsey A. Roth, Sam S. Oh, Harold J.Farber, Denise Serebrisky, Rajesh Kumar, Luisa N. Borrell, Emerita Brigino-Buenaventura, Adam Davis, Michael A. LeNoir, Kelley Meade, William Rodriguez-Cintron, Pedro C. Avila, Jose R. Rodriguez-Santana, Saunak Sen, Fred Lurmann, John R.Balmes, Esteban G. Burchard. Early Life Exposure to Air Pollution and the Risk ofAsthma in Latino and African American Children. ARJCCM. (Submitted January 2013).48

Sandler Asthma Basic REsearch CenterCore FacilitiesCell Sorting and Analysis CoreDirector: Zhien-WangObjectiveFlow cytometry is necessary to characterize, purify and separate cell types based on surfacecharacteristics. The objective of this core is to provide technical support and access to highlysophisticated instruments for persons at UCSF performing asthma-related research.Contributions from SABRE Center have been partnered with the Diabetes Center, individualinvestigator resources and institutional resources to support the space and maintenance of thecore largely through an integrated re-charge system. Students and postdocs participate intraining in the core at an area where training can be centralized in order to facilitate maintenanceand oversight.AccomplishmentsThe Core is located in S1067 in proximity to Dr. Locksley’s laboratory and centrally within theImmunology Program corridor above the SABRE Center space in HSE201. Scheduling is onlineand suitably trained individuals can access instruments in the core 24 hours a day, 7 days aweek.The space offers an array of instrumentation that offers unique capabilities in data acquisitionand enhances the depth of technical capacity:Two Beckman-Coulter MoFlo XDP High-Speed sorters with 4-laser, 17-color, 15-parametercapability centered around 488 nm, 532 mm, 561 mm and 647 nm multi-line air-cooled lasers.Two side-by-side instruments has enabled operation by a single individual, thus optimizing useand minimizing cost.Becton-Dickinson Biosciences LSR II Flow Cytometer with 4-laser, 10-color, 12-parametercapability centered around 488 nm OPSL, 637 nm (red), 403 nm (violet) and 535 nm (green)lasers. Total use > 1600 hrs.Becton-Dickinson Biosciences LSR II Flow Cytometer with 4-laser, 10-color, 12-parametercapability centered around 488 nm OPSL, 637 nm (red), 403 nm (violet) and 535 nm (green)lasers is maintained by the core but stationed in HSE201 in the SABRE core space. Total use >800 hrs.Training and Integration with Sandler ProgramUse of the core has stabilized over the past 2 years. Over the last 12 months, >45 laboratories atthe UCSF Parnassus and Mission Bay campuses have used the facility 2 or more times, with 32labs over 3 times. In turn, the numbers of users per laboratory has also stabilized at 2.3 users/lab,and reflects use by graduate students and postdocs. Nine of the labs are direct participants in theSABRE Center, and a number of the other users are affiliated investigators examining aspects of49

Sandler Asthma Basic REsearch CenterCore Facilitiesinflammation and tissue injury of relevance to asthma. All of the core SABRE Center scientistsparticipate in the Sorting Core. Budgetary requests from the SABRE Center are now restrictedto acute laser failure and maintenance, as personnel and renewables have all been coveredthrough recharge mechanisms.Grants and PublicationsData acquired in the Cell Sorting and Analysis core has contributed to almost a quarter of thepublications listed in the bibliography for the current annual report.50

Sandler Asthma Basic REsearch CenterCore FacilitiesMicroscopy CoreManaging Director: Kaitlin CorbinFaculty Director: Matthew Krummel, Ph.D.Objective/MandateThe objective of the SABRE Microscopy Core is to advance light-based imaging of the lung andassociated tissues. Our core operates under the premise that a critical understanding of diseasedtissues and organs such as the asthmatic lung will come with the study of the activities ofcomponent players (cell types, effector molecules) in their native environment. We alsorecognize that many existing imaging methods may require some additional development orelaboration before they can be successfully applied in studies of lung biology. We act both as arepository/resource of imaging technology and expertise and to develop novel technologies. Werepresent an emerging evolving example of a ‘Co-laboratory’ in which expertise in this activearea of scientific progress is shared rather than arbitrarily monetized.Strategic GoalsThe efforts of this center are being directed toward improved imaging technologies for cells ofthe normal and allergic lung. In 2013, the core will be trying to advance three specific goals forintravital imaging. Note that in the 2012 period, we have miniaturized and made less-invasiveour lung-stabilization rigs, have implemented a new microscope with photoablation andphotoactivation capability and have optimized mouse models for imaging increased numbers ofcell types at the same time.1. To provide stabilized access to larger airways and trachea of living mice, using astabilized gradient- refractive index (GRIN) lens.2. To develop software processing platforms for converting >100GB datasets into imagesand parametrized object-based data for rapid scoring of immune and cell-cell dynamicswithin large and long-time course experiments.3. To provide improved surgical stabilization to image lungs over many days withrepeated visits to the same regions.4. To extend usage of the human lung imaging method through expanded facility capacityand training/sample processing capabilities and through collaboration with asthmaresearchers with access to primary biopsy material.5. To provide ongoing technical and instrumentation support to the UCSF (and beyond)Asthma community in order to put existing and emerging imaging technologies topractical use in the study of asthma.51

Sandler Asthma Basic REsearch CenterCore FacilitiesPhotoablation and Photoactivation: In 2012, we extensively tested and subsequently purchased,microscopes with both a single-photon and two-photon ablation lasers that now allow us topurposefully modulate biology in the lung using spots of light. This is being developed as a wayto determine which cells are critical for the ongoing biology in allergic lungs. We were able toobtain grant money for this (NIH S10) as a result of preliminary data generated in this SABREfundingfacility.Introduction of demo equipment, (see below) and establishment of SOPs and training.This year, we served as a demo site for a Nikon ‘STORM’ microscope as well as the Zeiss&710MP. As with other demos in the past, we negotiated with vendors to ensure that equipmentwas onsite for at least one month (typically much longer).SpaceWe maintain instruments and development tools in three ‘core’ rooms in Medical Sciences S11and we also maintain additional microscopes in 6 additional sites throughout the campus,including behind the animal barrier.FundingThe following represent some of the lung-related grants which were funded in 2012, in partthrough our efforts and support:Sheppard/Woodruff/Erle/Krummel: NIH Headley:DoD Postdoctoral ($300K/yr 3 yrs)U01: AADCRC ($7.5M/5 years)Acerbi: Komen Postdoctoral ($60K/yr 3Maelig PBBR Postdoctoral ($10K/1yr)years)Maelig: DoD Postdoctoral ($300K/yr 3 yrs) Nystul: R01And these were submitted:Nishimura R01 resubmitted (likely funded)Looney/Krummel R01 submittedP.T. Chuang R01 submittedJ.S. Shin R01 submittedSchneider S10 submittedWerb R01 submittedWErb et al. PPG submittedRecent publicationsA number of recent and forthcoming publications, both methodological and research-orientated,have been produced with help of the facility during the past year. These include:1. Paszek MJ, DuFort CC, Rubashkin MG, Davidson MW, Thorn KS, Liphardt JT, WeaverVM. Scanning angle interference microscopy reveals cell dynamics at the nanoscale. NatMethods. 2012 Jul 1;9(8):825-7. doi: 10.1038/nmeth.2077. PubMed PMID: 22751201;PubMed Central PMCID: PMC3454456.2. Zhang Y, Chen YC, Krummel MF, Rosen SD. Autotaxin through lysophosphatidicacidstimulates polarization, motility, and transendothelial migration of naive Tcells. J53

Sandler Asthma Basic REsearch CenterCore Facilitiesquantify data has reached a limit with current tools. Our in-house software programmer, HenryPinkard, has been developing methods to rapidly parameterize data to reduce complexity forfeature-tracking and analysis of cell-cell contacts. This work will expand in 2012.3. In 2012, we will be taking two steps toward applying subcellular imaging to human tissuesdirectly. First, we are continuing to evolve a ‘live biopsy’ method. Second, we are collaboratingwith the local and recently funded AADCRC (NIH Asthma consortium) to develop novel proteinaffinity reagents to specifically label and track key populations within the lung. This work willexpand into supporting imaging of bronchial pinch biopsies over the next five years.4. We plan to continue to provide ongoing technical and instrumentation support to the UCSF(and beyond) Asthma community in order to put existing and emerging imaging technologies topractical use in the study of asthma.Training and Integration with Sandler ProgramAs noted in previous updates, the center aims to provide ongoing technical and instrumentationsupport to the UCSF (and beyond) Asthma community. Specifically our goal is to put existingand emerging imaging technologies to practical use in the study of asthma. This year, we havespecifically undertaken training of Peck and Wong in performing lung-based assays from start tofinish so that they may be able to undertake experiments for/with new users that may not haveexperience with these assays. This is particularly important in some of the more complicatedprocedures in which technical expertise is critical to the success of the experiment.We have taught live lung imaging techniques to visitors from Michael Cahalan’s lab (UC Irvine)and from Paul Kubes’ lab (University of Calgary).To introduce imaging advances within the wider community, the core also sponsors a recurringpizza-talk at which groups from the Bay Area and beyond present novel imaging technology andadvances. Topics this year have included live lung imaging, 3D printing and design, Multidimensionalanalysis, and in vivo optical imaging. Details can be seen at the website:http://pathology.ucsf.edu/BIDC//seminars.html.Current EquipmentPermanent Equipment:1. Gen1 custom built 2-photon: 4 color2. Gen2 custom built 2-photon: 5 color3. *Gen3 custom built 2-photon: 8 color/2 laser (being elaborated with a DMD array forphoto-activation/ablation)4. *Spectral laser scanning confocal microscope (C1Si)5. Spinning-disk confocal microscope (Yokogawa 4-laser on a Zeiss 200M base)6. Upright Zeiss microscope set up for fluorescence interference contrast imaging.7. Zeiss Axiovert 100 timelapse microscope55

Sandler Asthma Basic REsearch CenterCore Facilities8. IVIS live animal imager (animal colony)9. Nikon spinning-disk confocal with TIRF and photo-ablation (Wittman)10. Zeiss Cell Observer with Apotome (Nystul)11. *Alaris 3D printer12. Nikon A1R Multiphoton microscope.* Indicates SABRE is a partial owner of this instrument.Additional Equipment hosted on-site in 2012:1. Zeiss 710 Multi-photon confocal microscope2. Nikon ‘STORM’ ,microscope.Analysis Computers and Software Platforms:This year, as a result of increased demand, we purchased a third IMARIS license and associatedMatlab license and increased our workstations to four, installing a new desk to house this. Aspart of a cooperative agreement, MDS/Molecular Devices again supplied upgraded keys for PCbasedanalysis stations for image processing. We have partnered with and will support thefollowing commercial partners who supply working copies of their software as part of thesponsorship program:• MDS/Molecular Devices 'Metamorph' (who are supplying the three offlinecomputers/keys as well as online keys)• Bitplane 'Imaris' (who have subsidized the purchase of software used in the facility).• Solidworks who have supplied 2 discounted software keys for our manufacturingpurposes.56

Sandler Asthma Basic REsearch CenterAsthma Related Research ProjectsASTHMA RELATED RESEARCH PROJECTS57

Sandler Asthma Basic REsearch CenterAsthma Related Research ProjectsEvolving Microenvironments in Airway InflammationProgram Director: George H. Caughey, M.D.Program Project Grant HL024136 is nearing completion of its 33nd year, the third of a plannedfive years of interdisciplinary study of airway inflammation competitively renewed on May 11,2010. Each of the component projects focuses on different populations of airway cells andmolecules mediating structural changes in the airway accompanying chronic airwayinflammation. The Projects are supported by two Cores, one administrative and one scientific(Tools for Analysis of Airway Inflammation).Summary of Advances this YearProject 1: Roles of Peptidases in Chronic Airway Inflammation (Project Leader: G.H. Caughey)One of Project 1’s major achievements was identification of a substrate andspectrophotometric technique allowing direct assay of prostasin activity in living humanairway epithelial apical and basolateral surfaces. Using this substrate in conjunction withselective inhibitors, we established that prostasin anchored to the cell surface by a lipid(glycosylphosphatidylinositol) is the major contributor to surface activity. For example, theapical surface of cultured human bronchial epithelial cells expresses 22% of total,extractable, aprotinin-inhibitable, tryptic activity and 16% of prostasin immunoreactivity.Similar results were obtained using cultured cystic fibrosis bronchial cells. Thus, weestablished that prostasin is present, mature and active on the apical surface of wild type andcystic fibrosis bronchial epithelial cells, where it can be targeted for inhibition via theairway lumen with the goal of inhibiting epithelial Na+ uptake and therapeuticallyincreasing hydration of airway secretions. We also established differences betweenprostasins (mouse and human) and other surface epithelial tryptic proteases (matriptase andmarapsin) in peptide cleavage preferences, inhibitor susceptibility, and modes of membraneanchoring. In contrast to mouse “knockouts” of prostasin and matriptase, a mouse wecreated that is genetically deficient of marapsin/Prss27 is fully viable, further supportingdifferent roles despite similar high degrees of evolutionary conservation in vertebrateanimals. Additional significant progress was made in testing our hypothesis that variationsin inheritance of active tryptase genes is common and that inheritance of dysfunctionalalleles is protective with respect to asthma phenotypes.Project 2: Imaging T cell Airway Responses during Inflammation (Project Leader: M.F. Krummel)In this year of funding, we established a labeling method for tracking and imaging incomingmonocytes using two genetically-encoded fluorescent proteins. We are now tracking in real-timethe differentiation of these cells as they move from alveoli towards airways. Our goal is toreveal key checkpoints that might be exploited for modulating asthma severity and this is a directoffshoot of Aim 1 of this proposal. In a second project driven by our Aim 2, we are tracking thesite of Th2 differentiation in asthma models. Preliminary data on this front suggests that IL-4secretion is first found in lung, suggesting that dendritic cell-T cell interactions at that sitemodulate the response. Related to this, in the coming year, we will complete our study of therelative sites and dynamics of Th2 and regulatory (Treg) cells in asthma models. Finally, we58

Sandler Asthma Basic REsearch CenterAsthma Related Research Projectsbegan pilot work to examine interactions of allergic T cells with neurons and neuroendocrinecells in the allergic lung.Project 3: Lymphangiogenesis and Angiogenesis in Airway Inflammation (Project Leader: D.M.McDonald)During the past year, an important focus of Project 3 was to determine the extent anddistribution of lymphangiogenesis in the inflamed lung and the principal growth factors thatdrive it. Studies revealed that lung lymphatics increased 5-fold within 2 weeks afterMycoplasma pulmonis infection in mice. Strikingly, most of the new lymphatics were locatedwithin bronchus-associated lymphoid tissue (BALT) around large bronchi, pulmonaryarteries, and pulmonary veins. Few lymphatics were located near distal airways or alveoliunder normal conditions or in chronic inflammation. By using selective inhibitors of VEGFR-2 and VEGFR-3, experiments revealed that VEGFR-3 signaling was the dominant drivingmechanism for lymphangiogenesis after M. pulmonis infection. Because VEGF-C andVEGF-D are the principal ligands for VEGFR-3, these growth factors are likely to mediatelymphangiogenesis under these conditions. VEGFR-2 signaling could make a minorcontribution, but the underlying mechanism is still under investigation. VEGF-A appears notto have a significant contribution to lymphangiogenesis in the lung in this model. An essentialrole of VEGFR-3 signaling in lymphangiogenesis in the respiratory tract was also found in atransgenic mouse model, where IL-1b is overexpressed in the epithelium under doxycyclineregulation. Here, lymphatic growth was completely blocked by sequestration of the VEGFR-3 ligands VEGF-C and VEGF-D. Because of this key involvement of VEGF-C or VEGF-D,the role of IL-1b was explored further by determining the location of IL-1R1 receptor. Thesewere found to be preferentially located on epithelial basal cells and neuroendocrine cells, atleast under normal conditions. The identification of factors that link these epithelial targets ofIL-1b to the cellular sources of VEGF-C and VEGF-D is underway. Chemokines that recruitmacrophages are being explored as candidates.Scientific Core ActivitiesIn this year of funding, we generated new and tittered stocks of mycoplasma for use in thethree projects and the Core continues to function in performing genotyping of key mousestrains. The Core also has performed and continues to perform confocal and 2-photonimaging experiments in addition to assisting in keeping these instruments maintained andoptimized. Personnel funded by this core component have also permitted pilot projects ontryptase and protease functions in airway remodeling, in neuroendocrine cells and in thedynamics of T cell-dendritic-mast cell interactions. In the next year, the core will alsocontribute to an effort to perform high-resolution intravital imaging of mouse trachea.Training and Integration with the Sandler ProgramThe SABRE Center continues to provide a focus to bring together all of the groups studyingfundamental questions relevant to asthma at UCSF. This focus includes a monthly researchmeeting of investigators with asthma-focused basic research. The Sandler-supported core alsoprovided advice and training in sensitization and challenge protocols for creating mouse models59

Sandler Asthma Basic REsearch CenterAsthma Related Research Projectsof chronic allergic inflammation and for monitoring changes in airway resistance. It alsofacilitated sharing of models and advanced imaging technologies.P01 HL024136-supported selected publications (2012-2013)1. Baluk P, Hogmalm A, Bry M, Alitalo K, Bry K, McDonald DM. Transgenicoverexpression of interleukin-1b induces persistent lymphangiogenesis but notangiogenesis in mouse airways. Am J Pathol (in press).2. Banfi A, von Degenfeld G, Gianni-Barrera R, Reginato S, Merchant MJ, McDonaldDM, Blau HM. Therapeutic angiogenesis due to balanced single-vector delivery ofVEGF and PDGF-BB. FASEB J 26:2486-97, 2012, PMID 22391130; PMCIDPMC3360154.3. Caughey GH. “Chymases” in Handbook of Proteolytic Enzymes, 3 rd edition,Rawlings N and Salvesen G, eds., Elsevier, Oxford, in press.4. Caughey GH. “Mastins” in Handbook of Proteolytic Enzymes, 3 rd edition,Rawlings N and Salvesen G, eds., Elsevier, Oxford, in press.5. Cheng LE, Hartmann K, Roers A, Krummel MF, Locksley RM. Perivascular mastcells dynamically probe cutaneous blood vessels to capture Immunoglobulin E.Immunity (in press), PMID 23290520.6. Greenland JR, Jones KD, Hays SR, Golden JA, Urisman A, Jewell NP, CaugheyGH, Trivedi NN. Association of large-airway lymphocytic bronchitis withbronchiolitis obliterans syndrome. Am J Resp Crit Care Med, 187:417-23, 2013;PMID 23239157.7. Nimishakavi S, Besprozvannaya M, Raymond WW, Craik CS, Gruenert DC,Caughey GH. Activity and inhibition of prostasin and matriptase on apical andbasolateral surfaces of human airway epithelial cells. Am J Physiol Lung Cell MolPhysiol 303:L97-106, 2012; PMID 22582115.8. Orsenigo F, Giampietro C, Ferrari A, Corada M, Galaup A, Sigismund S, Ristagno G,Maddaluno L, Young Koh G, Franco D, Kurtcuoglu V, Poulikakos D, Baluk P,McDonald D, Grazia Lampugnani M, Dejana E. Phosphorylation of VE-cadherin ismodulated by haemodynamic forces and contributes to the regulation of vascularpermeability in vivo. Nat Commun 3:1208, 2012, PMID 23169049; PMCIDPMC3514492.9. Raman K, Caughey GH. “Marapsin” in Handbook of Proteolytic Enzymes, 3 rdedition, Rawlings N and Salvesen G, eds., Elsevier, Oxford, 2013.10. Raman K, Trivedi NN, Raymond WW, Ganesan R, Kirchhofer D, Verghese GM, CraikCS, Schneider EL, Nimishakavi S, Caughey GH. Mutational tail loss is an evolutionarymechanism for liberating marapsins and other type I serine proteases from transmembraneanchors. J Biol Chem, in press.11. Sennino B, Ishiguro-Oonuma T, Wei Y, Naylor RM, Williamson CW, Bhagwandin V,Tabruyn SP, You WK, Chapman HA, Christensen JG, Aftab DT, McDonald DM.Suppression of tumor invasion and metastasis by concurrent inhibition of c-met andVEGF signaling in pancreatic neuroendocrine tumors. Cancer Discov 2:270-87, 2012,PMID 22585997; PMCID PMC3354652.12. Sennino B, McDonald DM. Controlling escape from angiogenesis inhibitors. Nat Rev60

NIAID Asthma and Allergic Disease Cooperative Research CenterPrincipal Investigator, Dean SheppardObjectiveThe major goal of this multi-project U19 Center Grant is to bring studies using human materialsand genetically modified mice together in innovative ways in order to define the overlapping anddistinctive roles for the cytokines IL-13 and IL-17 in airway pathology of relevance to humanasthma. This U19 was successfully renewed after an initial five year funding period, to extendour total recognition as an AADCRC to 10 years.Specific AimsOver the past decade, work from several centers, including our own, has identified critical rolesfor the effector cytokines, IL-13 and IL-17, in multiple models of allergic asthma. Recent datademonstrating the effectiveness of IL-13 inhibition in a subset of patients with asthma confirmsthe importance of this cytokine in the human disease. The demonstration that circulating levelsof IL-17 and circulating Th17 cells correlate with asthma severity also support a role for IL-17 inpatients. It is now clear that IL-13 and IL-17 can be produced by multiple hematopoietic cells inthe airways, but that they exert their major disease-producing effects by acting directly onresident airway cells – principally airway epithelial cells and airway smooth muscle. During thecurrent funding period of this AADCRC, we have used mice engineered to mark cytokineproducingcells to identify key roles for innate helper cells (iH2 cells) and Th2 cells as early andsustained sources of IL-13 in allergic airways. We have also identified an important role forantigen-specific alpha-beta T cells as key effectors of airway hyperresponsiveness anddemonstrated that IL-17A released by these cells acts directly on murine (and human) airwaysmooth muscle to enhance contractility through induction of the small GTPase, RhoA and itseffector kinase, ROCK2. Finally, we have identified characteristic mRNA expression signaturesand a large number of miRNAs differentially expressed in cytokine-stimulated airway epithelialcells, work that has allowed identification of a subset of patients with asthma (Th2 high) whorespond favorably to treatment with IL-13 inhibitors. Work in the current funding period hasstrongly suggested that IL-13 and IL-17 act locally on airway epithelium and airway smoothmuscle, and has pointed to the importance of identifying where and when each cytokine is madeand released. It is also clear that we need to know which resident cells are the critical responders,and how these responses are regulated in individual patients. The current renewal is organizedaround 3 Projects driven by 3 Principle Investigators together with a Clinical Subjects andBiospecimen Core for standardizing the conjoined approaches.There are threee Specific Aims associated with the Grant:1. To identify critical miRNAs that are differentially expressed in the airway epithelium ofpatients with asthma at baseline and in response to allergen challenge or corticosteroidtreatment, to determine the roles of IL-13 and IL-17 in regulating these miRNAs and toidentify miRNAs that mediate cytokine-induced mucous metaplasia. (PI: David Erle)2. To determine the relative importance of responses of airway smooth muscle andepithelium to IL-17 in the induction of airway hyperresponsiveness and to determine the62

individual and combined effects of IL-13 and IL- 17 on airway smooth musclecontractility and on clinical responses of patients with severe and mild-to-moderateasthma and in response to allergen challenge. (PI: Dean Sheppard)3. To determine the temporal and spatial dynamics of the interactions of IL-13 and IL-17producing cells with antigen-presenting cells and with airway epithelium and airwaysmooth muscle in lung slices from allergen challenged mice and in human airwaybiopsies from patients with severe and mild-to-moderate asthma and in response toallergen challenge or treatment with corticosteroids. (PI: Matthew Krummel)The proposed studies will draw heavily from our large on-going clinical studies in patients withasthma and from the extensive experience of carefully collecting and utilizing biospecimensfrom these subjects by Prescott Woodruff, the PI and director of the Clinical Subjects andBiospecimen Core for the Grant. The work will benefit from the extensive experience withmicroarray and miRNA analysis and the study of mucous metaplasia in human airwayepithelium by David Erle, Project Leader of Project 1. We will also benefit from the experienceof Dean Sheppard, PI and Project Leader of Project 2 in functional assessment of airway smoothmuscle from mice and humans. Finally, we will draw on pioneering approaches to intravitalmicroscopy in lung slices and human airway tissue, developed by Max Krummel, the ProjectLeader of Project 3. Through our joint efforts, we hope to better understand the dynamics ofcytokine release and effects in the asthmatic airway, to develop new strategies to identifyclinically relevant sub-phenotypes in asthma, and to develop broadly useful methods to mark anddynamically follow antigen-specific T cell sub-types in readily accessible biopsies from patientswith asthma. In addition to addressing the specific important questions raised by this proposal,we expect these methods to be widely useful to investigators in each of the other nationwideAsthma and Allergic Diseases Cooperative Research Centers and to other investigators interestedin allergic airway diseases.Training and Integration with the Sandler CenterThis Center Grant provides training in basic biology and genetics of asthma for approximatelypost-doctoral fellows and graduate students working in the labs of the project directors. Theleaders of each of the Projects and the Core are already actively involved in SABRE. Much ofthe preliminary data that served as the basis for this successful application was generated at leastin part through support from SABRE. The studies using murine models of asthma that suppliedpreliminary data for project 2 were performed in the SABRE mouse physiology and morphologycore and the human genetic studies were performed together with the SABRE human geneticscore. Drs. Erle and Krummel, leaders of projects 1 and 3, have each received SABRE Innovativegrants in the past that contributed to generation of the preliminary data supporting their project.The infrastructure developed with SABRE participation for the Airway Clinical Research Centerprovided a critical aspect of support for this grant. This Center grant would not have been likelyto succeed without this extensive support from SABRE and thus represents a clear example ofleveraging SABRE funds to further enhance research into the basic mechanisms underlyingasthma.63

Approved Funding for this AwardThis program project provides between $1.1 and $1.2 million in direct costs per year for 5 years,with a total indirect and direct over the 5 years of $8,642,948.64

Sandler Asthma Basic REsearch CenterContributions to Relevant Scientific ActivitiesCONTRIBUTIONS TO RELEVANTSCIENTIFIC ACTIVITIES65

Sandler Asthma Basic REsearch CenterImmunology Seminar Series2012-2013 ScheduleMondays, 9amRoom: N-217Date Speaker HostSeptember 10 Amy Weinmann Mark AnselSeptember 17 Christopher Garcia Lewis LanierSeptember 24 Thaddeus Stappenbeck Averil MaOctober 1 Julie ZikhermanOctober 8 Taka Okada Mark AnselOctober 15 Harry Greenberg Mike McCuneOctober 22 Markus Müschen LowellOctober 29 Paul Crocker Jason CysterNovember 5 Andre Veillette Cliff LowellNovember 12 No SeminarNovember 19 Doreen Cantrell Art WeissNovember 26 No SeminarDecember 3 Erin Adams Frances BrodskyDecember10 Larry Samelson Art WeissDecember 17 Glenn Dranoff Lewis LanierJanuary 7 Boris Reizis Anthony DeFrancoJanuary 14 Mike Dustin Matthew KrummelJanuary 28 Hozefa Bandukwala Anthony DeFrancoFebruary 4 Emil Unanue Jeoung-Sook ShinFebruary 11 Hugh Rosen Matthew KrummelFebruary 25 Patrick Wilson Jason CysterMarch 4 David Underhill Cliff LowellMarch 11 Ann Marshak-Rothstein Matthias WablMarch 18 Pam Schwatzberg Mark Ansel and Averil MaMarch 25 Victor Engelhard Mark AndersonApril 1 Georg Lauer Mike McCuneApril 8 Judy Lieberman Averil MaApril 15 Kees Murre Averil MaApril 22 Judith Hellman - UCSFApril 29 John O’Shea Ansel /MaMay 6No SeminarMay 13 Hidde Ploegh Art Weiss66

Sandler Asthma Basic REsearch CenterUCSF PULMONARY RESEARCH CONFERENCE 2012-2013Mondays, 5:00 pm - Parnassus HSW-303Date Talk 1 (Clinical) Talk 2 (Basic) Moderator09/10/12 Anthony Shum Kamran Atabai Luke Davis09/17/12 Ted Omachi Nirav BhaktaDean Sheppard09/24/12 Erin Gordon Ed Ostrin Hal Collard10/01/12 Madori Kato-Maeda Suzaynn Schick Luke Davis10/08/12 Jon Singer Eric Seeley Prescott Woodruff10/15/12 Christina Yoon Mike LaFemina Luke Davis10/22/12 Yvonne Huang Aparna Sundaram Prescott Woodruff10/29/1211/05/12 Stephanie ChristensonCVRI Retreat (no conf)Dario Barbone James Frank11/12/1211/19/12 Neeta ThakurHolidayDara Torgerson Mallar Bhattacharya11/26/12 John Greenland Shaopeng (Leo) Yuan Mallar Bhattacharya12/03/12 Rama Mallampalli, MD (Visiting Professor)Prescott Woodruff12/10/12 Nuala Meyer, MD (Assistant Professor from Pennsylvania sponsored by M.Matthay) Michael Matthay12/17/12 Neil Trivedi Maria Del Mar Del Pino Yanes Hal Collard12/24/1212/31/1201/07/13Winter holidayWinter holidayLandon King, MD (Visiting Professor)James Frank01/14/13 Charles Everett Peter Haggie Mallar Bhattacharya01/21/1301/28/13Martin Luther King holiday (no conf)Fellows feedback (no conf)Luke Davis (cancel)02/04/13 Julian Solway, MD (Visiting Professor)Paul Wolters02/11/13 Robert Su Vikash Bhagwandin Prescott Woodruff02/18/1302/25/1303/04/13 Payam NahidPresident's Day holiday (no conf)Bruce Levy, MD (Visiting Professor)Luke Bonser03/11/13 Kirsten Kangelaris Chun Chen Luke Davis03/18/13 Elizabeth Fair Anirban Datta Hal Collard03/25/13 Chris Gignoux Andrew Vaughan Hal Collard04/01/13 Serpil Erzurum (Visiting Professor)Paul Wolters04/08/13 John Metcalfe Alexandra Greer Luke Davis04/15/1304/22/13 Noah ZaitlenDarrell Kotton, MD (Visiting Professor)Binh Diep Prescott Woodruff04/29/13 Misha Agarwal Marrah Lachowicz-Scroggins Prescott Woodruff05/06/13 Xiang Xu Hassan Lemjabbar-Alaoui James Frank05/13/13 Sam Oh Mallar Bhattacharya Prescott Woodruff05/20/1305/27/1306/03/13 Josh GalanterATS Conf (no conf)Memorial Day holiday (no conf)John Li Mallar Bhattacharya06/10/13 Robert Blount Katherine Nishimura Mallar Bhattacharya06/17/1306/24/13Fellows feedback (no conf)Year end party67

Sandler Asthma Basic REsearch Center SABRE Asthma Research Conference ScheduleLocation: 513 PARNASSUS AVENUE, HSE-13032 nd Thursday of the Month for 2012 at 4 P.M.2 nd Monday of the Month for 2013 at 3 P.M.DatePresenter9/13/2012 Limin Liu, PhD10/11/2012 Chris Allen, PhD11/8/2012 Max Krummel, PhD12/13/2012 Esteban Burchard, MD, MPH2/11/2013 Kamran Atabai, MD3/11/2013 Mark Ansel, PhD4/8/2013 John Fahy, MD5/13/2013 Richard Locksley, MD6/10/2013 Jeoung-Sook Shin, PhD7/8/2013 David Erle, MD8/12/2013 Laurence Cheng, MD, PhD9/9/2013 Herbert DeBroski10/14/2013 Prescott Woodruff, MD, MPH11/18/2013 Dean Sheppard, MD12/9/2013 Chris Allen, PhD68

Immunology Seminar Series"Imaging of cross-presenting dendritic cellsin the lymph node”Takaharu Okada, Ph.D.Unit Leader, Research Unit for ImmunodynamicsResearch Center for Allergy & ImmunologyRiken JapanMonday, October 8, 20129am, Parnassus, N-­‐‐225Host: Mark Ansel (mark.ansel@ucsf.edu)BROADCAST | Mission Bay, Genentech Hall S-­‐‐271 § /presentations/live § SPONSORS | Gladstone Institute of Virology &Immunology § Rosalind Russell Medical Research Center for Arthritis § Sandler Asthma Basic Research Center, SABRE –INFORMATION (415) 502-­‐‐1961 http://www.ucsf.edu/immuno Live stream and archive available (UCSF MyAccess login required)69

Sandler Asthma Basic REsearch Center70

Sandler Asthma Basic REsearch CenterRecent and New PublicationsRECENT AND NEW PUBLICATIONSSUPPORTED BY THE SANDLER ASTHMABASIC RESEARCH CENTER(2011-2013)71

Christopher C.D. Allen, Ph.D.Beltman JB, Allen CDC, Cyster JG, de Boer RJ (2011). B cells within germinal centers migratepreferentially from dark to light zone. Proceedings of the National Academy of Sciences,108(21), 8755-8760. PMCID: PMC3102384Green JA, Suzuki K, Cho B, Willison LD, Palmer D, Allen CDC, Schmidt TH, Xu Y, Proia RL,Coughlin SR, Cyster JG (2011). The sphingosine 1-phosphate receptor S1P 2 maintains thehomeostasis of germinal center B cells and promotes niche confinement. Nature Immunology,12(7), 672-680. PMCID: PMC3158008.Sullivan BM, Liang HE, Bando JK, Wu D, Cheng LE, McKerrow JK, *Allen CDC, *LocksleyRM (2011). Genetic analysis of basophil function in vivo. Nature Immunology, 12(6), 527-535.*co-corresponding author. NIHMSID352031Steiner DF, Thomas MF, Hu JK, Yang Z, Babiarz JE, Allen CDC, Matloubian M, Blelloch R,Ansel KM (2011). MicroRNA-29 Regulates T-Box Transcription Factors and Interferon-γProduction in Helper T Cells. Immunity, 35(2), 169-181.Yang Z, Sullivan BM, Allen CDC (2012). Fluorescent in vivo detection reveals that IgE + B cellsare restrained by an intrinsic cell fate predisposition. Immunity, in press,doi:10.1016/j.immuni.2012.02.009K. Mark Ansel, Ph.D.Baumjohann D, Okada T, Ansel KM. Cutting Edge: Distinct Waves of BCL6 Expression duringT Follicular Helper Cell Development. J Immunol.187:2089-92 (2011)Steiner DF, Thomas MF, Hu JK, Yang Z, Babiarz JE, Allen CD, Matloubian M, Blelloch R,Ansel KM. MicroRNA-29 Regulates T-Box Transcription Factors and Interferon-γ Productionin Helper T Cells. Immunity 35:169-81 (2011)Sofi MH, Qiao Y, Ansel KM, Kubo M, Chang CH. Induction and Maintenance of IL-4Expression Are Regulated Differently by the 3' Enhancer in CD4 T Cells. J. Immunol. 186:2792-9 (2011)Grégory Seumois, Pandurangan Vijayanand, Christopher J Eisley, Nada Omran, Lukas Kalinke,Mai North, Asha P. Ganesan, Laura J Simpson, Nathan Hunkapiller, Fleix Molzahan, Prescott GWoodruff, John V Fahy, David J Erle, Ratka Djukanovic, Robert Blelloch, K Mark Ansel: Anintegrated nano-scale approach to profile miRNAs in limited clinical samples. Am J Clin ExpImmuol. 1:70-89 (2012)Hoefig KP, Rath N, Heinz GA, Wolf C, Dameris J, Schepers A, Kremmer E, Ansel KM,Heissmeyer V. Eri1 degrades the stem-loop of oligouridylated histone mRNAs to inducereplication-dependent decay. Nat Struct Mol Biol. 20:73-81 (2013)Solberg OD, Ostrin EJ, Love MI, Peng JC, Bhakta NR, Hou L, Nguyen C, Solon M, Nguyen C,Barczak AJ, Zlock LT, Blaev DP, Finkbeiner WE, Ansel KM, Arron JR, Erle DJ, Woodruff PG.Airway Epithelial miRNA Expression is Altered in Asthma. Am. J. Respir. Crit. Care Med.186:965-74 (2012)Thomas MF, Abdul-Wajid S, Panduro M, Babiarz JE, Rajaram M, Woodruff P, Lanier LL,Heissmeyer , Ansel KM. Eri1 regulates microRNA homeostasis and mouse lymphocytedevelopment and anti-viral fuction. Blood. 120:130-42 (2012)Vijayanand P, Seumois G, Simpson LJ, Abdual-Wajid S, Baumjohann D, Panduro M, Huang X,Interlandi J, Djuretic IM, Brown DR, Sharpe AH, Rao A, Ansel KM. Interleukin-4 Production yFollicular Helper T Cells Requires the Conserved Il4 Enhancer Hypersensitivity Site V.Immunity 36:175-87 (2012)72

Homer Boushey, M.D.Huang YJ, Nelson CE, Brodie EL, DeSantis TZ, Baek MS, Liu J, Woyke T, Allaier M, BristowJ, Wiener-Kronish JP, Sutherland ER, King TS, Icitovic N, Martin RJ, Calhoun WJ, Castro M,Denlinger LC, DimangoE, Kraft M, Peters SP, Wasserman SI, Wechsler ME, Boushey HA, andLynch SV. Airway microbiota and bronchial hyperresponsiveness in patients with sub-optimallycontrolled asthma. JACI 2011; 127:372-381.Wootton SC, Kim DS, Kondoh Y, Chen E, Lee JS, Song JW, Huh JW, Taniguchi H, Chiu C,Boushey HA,Lancaster LH, Wolters PJ, Derisi J, Ganem D, Collard HR. “Viral Infection inAcute Exacerbation of Idiopathic Pulmonary Fibrosis.” Am J Respir Crit Care Med. 2011 Feb 25Havstad S, Wegienka G, Zoratti EM, Lynch SV, Boushey HA, Nicholas C, Ownby DR, JohnsonCC. "Effect of prenatal indoor pet exposure on the trajectory of total IgE levels in earlychildhood." Journal of Allergyand Clinical Immunology. 2011 Aug 4.McGrath KW, Icitovic N, Boushey HA, Lazarus SC, Sutherland ER, Chinchilli VM, Fahy JV;for the National Heart, Lung, and Blood Institute's Asthma Clinical Research Network of theNational Heart, Lung, and Blood Institute. "A Large Subgroup of Mild-to-Moderate Asthma isPersistently Non-Eosinophilic." Am J Respir Crit Care Med. 2012 Jan 20.Han MK, Huang YJ, Lipuma JJ, Boushey HA, Boucher RC, Cookson WO, Curtis JL, Erb-Downward J.Lynch SV, Sethi S, Toews GB, Young VB, Wolfgang MC, Huffnagle GB,Martinez FJ. "Significance of the microbiome in obstructive lung disease." Thorax. 2012 Feb 8.Calhoun WJ, Ameredes BT, King TS, Boushey HA. “Comparison of physician-based,biomarker-based, and symptom-based strategies for adjustment of inhaled corticosteroid therapyin adults with asthma: The Basalt Randomized Trial.” JAMA. 2012 Sept 12; 308:987-97.Esteban G. Burchard, M.D., M.P.H.Via, M, Gignoux C, Roth LA, Fejerman L, Galanter J, Choudhry S, Toro-Labradore G, Viera-Vera J, Oleksyke TK, Beckman K, Ziv E, Risch N, González Burchard E*, Martínez-CruzadoJC*. *These authors contributed equally to this manuscript. History shaped the geographicdistribution of genomic admixture on the island of Puerto Rico. PLoS One. 2011 Jan31;6(1):e16513.Galanter JM, Torgerson D, Gignoux CR, Sen S, Roth LA, Via M, Aldrich MC, Eng C,Huntsman S, Rodríguez-Santana J, Rodríguez-Cintrón W, Chapela R, Ford JG, Burchard, EG.Cosmopolitan and ethnic-specific replication of genetic risk factors for asthma in 2 Latinopopulations. J of Clinical Allergy & Immunology. 2011 Jul;128(1):37-43.Akuete K, Oh SS, Thyne S, Rodríguez-Santana J, Chapela R, Meade K, Rodríguez-Cintrón W,LeNoir M, Ford JG, Williams LK, Avila PC, Burchard EG†, Tcheurekdjian H†. EthnicVariability in Persistent Asthma after In Utero Tobacco Exposure. Pediatrics. 2011 In Press.†Shared senior authorship between Burchard and TcheurekdjianNHLBI EVE Asthma Genetics Consortium. Meta-analysis of genome-wide association studiesof asthma in ethnically diverse North American populations. Nat Genet. 2011 Jul 31.Bustamante CD, Burchard EG, De la Vega FM. Genomics for the world. Nature. 2011 Jul13;475(7355):163-5.Schauberger EM, Ewart SL, Arshad SH, Huebner M, Karmaus W, Holloway JW, Friderici KH,Ziegler JT, Zhang H, Rose-Zerilli MJ, Barton SJ, Holgate ST, Kilpatrick JR, Harley JB, Lajoie-Kadoch S, Harley IT, Hamid Q, Kurukulaaratchy RJ, Seibold MA, Avila PC, Rodriguez-CintrónW, Rodriguez-Santana JR, Hu D, Gignoux C, Romieu I, London SJ, Burchard EG, Langefeld73

CD, Wills-Karp M. Identification of ATPAF1 as a novel candidate gene for asthma in children.J Allergy Clin Immunol. 2011 Jun 20.Caleshu C, Sakhuja R, Nussbaum RL, Schiller NB, Ursell PC, Eng C, De Marco T, McGlothlinD, Burchard EG, Rame JE. Furthering the link between the sarcomere and primarycardiomyopathies: restrictive cardiomyopathy associated with multiple mutations in genespreviously associated with hypertrophic or dilated cardiomyopathy. Am J Med Genet A. 2011Sep;155A(9):2229-35. doi: 10.1002/ajmg.a.34097. Epub 2011 Aug 5. PMID: 21823217Kovacic MB, Myers JM, Wang N, Martin LJ, Lindsey M, Ericksen MB, He H, Patterson TL,Baye TM, Torgerson D, Roth LA, Gupta J, Sivaprasad U, Gibson AM, Tsoras AM, Hu D, EngC, Chapela R, Rodríguez-Santana JR, Rodríguez-Cintrón W, Avila PC, Beckman K, SeiboldMA, Gignoux C, Musaad SM, Chen W, Burchard EG, Hershey GK. Identification of KIF3Aas a novel candidate gene for childhood asthma using RNA expression and population allelicfrequencies differences. PLoS One. 2011;6(8):e23714. Epub 2011 Aug 30. PMID: 21912604.Kumar R, Tsai HJ, Hong X, Gignoux C, Pearson C, Ortiz K, Fu M, Pongracic JA, BurchardEG, Bauchner H, Wang X. African ancestry, early life exposures, and respiratory morbidity inearly childhood. Clin Exp Allergy. 2011 Sep 25. doi: 10.1111/j.1365-2222.2011.03873.x. PMID:22093077.Williams LK, Peterson EL, Wells K, Ahmedani BK, Kumar R, Burchard EG, Chowdhry VK,Favro D, Lanfear DE, Pladevall M. Quantifying the proportion of severe asthma exacerbationsattributable to inhaled corticosteroid nonadherence. J Allergy Clin Immunol. 2011 Oct 20.PMID: 22019090.Kenny EE, Timpson NJ, Sikora M, Yee MC, Moreno Estrada A, Eng C, Huntsman S, GonzalezBurchard E, Stoneking M, Bustamante CD, Myles S, Blond hair is caused by an amino acidchange in TYRP1. Science. 2012 May 4;336(6081):554George Caughey, M.D.Caughey GH. “Mast cell proteases as protective and inflammatory mediators”, in Mast CellBiology: Contemporary and Emerging Topics, Gilfillan AM and Metcalfe DD, eds., LandesBioscience, 2011.Caughey GH. “Protease mediators of anaphylaxis”, in Anaphylaxis and HypersensitivityReactions: From Molecular Markers to Rapid Desensitizations, Castells A, ed., Springer Inc.,2011.Xu X, Zhang H, Song Y, Lynch SV, Lowell CA, Wiener-Kronish JP, Caughey GH. Straindependentinduction of neutrophil histamine production and cell death by Pseudomonasaeruginosa. J Leuk Biol, in press, epub 2011.Sutherland SE. Xu X. Kim SS, Seeley EJ, Caughey GH, Wolters PJ. Parasitic infectionimproves survival from septic peritonitis by enhancing mast cell responses to bacteria in mice.PLoS One 6(11):e27564, 2011.Xu X, Zhang H, Song Y, Lynch SV, Lowell CA, Wiener-Kronish JP, Caughey GH. Straindependentinduction of neutrophil histamine production and cell death by Pseudomonasaeruginosa. J Leuk Biol 91:275-84, 2012.Sugimoto K, Kudo M, Sundaram A, Ren X, Huang K, Bernstein X, Wang Y, Raymond WW,Erle DJ, Åbrink M, Caughey GH, Huang X, Sheppard D. The α v β 6 integrin modulates airwayhyper-responsiveness in mice by regulating intra-epithelial mast cells. J Clin Invest 122:748-58, 2012.74

Nimishakavi S, Besprozvannaya M, Raymond WW, Craik CS, Gruenert DC, Caughey GH.Activity and inhibition of prostasin and matriptase on apical and basolateral surfaces ofhuman airway epithelial cells. Am J Physiol: Lung Cell Mol Physiol 303:L97-106, 2012.Greenland JR, Jones KD, Hays SR, Golden JA, Urisman A, Jewell NP, Caughey GH, TrivediNN. Association of large-airway bronchitis with bronchiolitis obliterans syndrome. Am JRespir Crit Care Med, in pressHarold Chapman, M.D.Marmai C, Sutherland RE, Kim KK, Dolganov GM, Fang X, Kim SS, Jiang S, Golden JA,Hoopes CW, Matthay MA, Chapman HA, Wolters PJ. Alveolar Epithelial Cells ExpressMesenchymal Proteins in Patients With Idiopathic Pulmonary Fibrosis. Am J Physiol LungCell Mol Physiol 2011, 301:L71-8. PMID: 21498628Chapman HA, Li X, Alexander JP, Brumwell A, Lorizio W, Tan K, Sonnenberg A, Wei Y,Vu T. Integrin α6β4 identifies an adult distal lung epithelial population with regenerativepotential in mice. J Clin Invest. 2011, 121:2855-62. See Commentary same issue.Ulsamer A, Wei Y, Kim KK, Tan K, Wheeler S, Xi Y, Thies RS, Chapman HA. Axinpathway activity regulates in vivo pY654-b-catenin accumulation and pulmonary fibrosis. JBiol Chem 2012, 287: 5164-5172.Sennino B, Ishiguro-Oonuma T, Wei Y, Naylor RM, Williamson CW, Bhagwandin V,Tabruyn SP, You WK, Chapman HA, Christensen JG, Aftab DR, McDonald DM.Suppression of tumor invasion and metastasis by concurrent inhibition of c-Met and VEGFsignaling in pancreatic neuroendocrine tumors. Cancer Discovery 2012, 2:270-287.Xi Y, Wei Y, Sennino, Ulsamer A, Kwan I, Brumwell AN, Tan K, Aghi MK, McDonald DM,Jablons DM, Chapman HA. Identification of pY654-b-catenin as a critical co-factor inhypoxia-inducible factor-1a signaling and tumor responses to hypoxia. Oncogene 2012, Dec17. doi: 10.1038/onc.2012.530.Smith KR, Dahl HH, Canafoglia L, Andermann E, Damiano J, Morbin M, Franceschetti S,Cossette P, Saftig P, Grötzinger J, Schwake M, Andermann F, Staropoli JF, Sims KB, MoleSE, Alexander NA, Cooper JD, Chapman HA, Carpenter S, Berkovic SF, Bahlo M.Cathepsin F mutations cause type B Kufs disease, an adult-onset neuronal ceroidlipofuscinosis. Human Molecular Genetics 2013, Jan 12. [Epub ahead of print].Anthony DeFranco, Ph.D.Hou B, A Benson, L Kuzmich, AL DeFranco and F Yarovinsky (2011). Critical coordinationof innate immune defense against Toxoplasma gondii by dendritic cells responding via theirToll-like receptors. Proc. Natl. Acad. Sci. USA 108: 278-283. PMC3017180Hou B, P Saudan, G Ott, ML Wheeler, M Ji, L Kuzmich, LM Lee, RL Coffman, MF Bachmann,A L DeFranco (2011). Selective utilization of Toll-like receptor and MyD88 signaling in Bcells for enhancement of the anti-viral germinal center response. Immunity 34: 375-84.PMC3064721.Scapini P, Lamagna C, Hu Y, Lee K, Tang Q, DeFranco AL, Lowell CA. (2011) B cellderivedIL-10 suppresses inflammatory disease in Lyn-deficient mice. Proc. Natl. Acad Sci.108: E823-832. PMC3193193Gross AJ, I Proekt and AL DeFranco (2011). Elevated BCR signaling and decreased survivalof Lyn-deficient transitional and follicular B cells. Eur. J. Immunol. 41: 3645-3655. PMC inprocess.Wheeler ML, and AL DeFranco (2012). Prolonged production of reactive oxygen species inresponse to BCR stimulation promotes B cell activation and proliferation. J. Immunol. 189:4405-16.75

Kirkland D, A Benson, J Mirpuri, R Pifer, B Hou, AL DeFranco, F Yarovinsky B cell-intrinsicMyD88 signaling prevents the lethal dissemination of commensal bacteria during colonicdamage (2012). Immunity 36: 228-238. PMC3288553.David Erle, M.D.Ritner C, Wong SS, King FW, Mihardja SS, Liszewski W, Erle DJ, Lee RJ, Bernstein HS. Anengineered cardiac reporter cell line identifies human embryonic stem cell-derived myocardialprecursors. PLoS One. 2011 Jan 4;6(1):e16004. PMID: 21245908Wang BT, Ducker GS, Barczak AJ, Barbeau R, Erle DJ, Shokat KM. The mammalian target ofrapamycin regulates cholesterol biosynthetic gene expression and exhibits a rapamycin-resistanttranscriptional profile. Proc Natl Acad Sci USA 108:15201-6, 2011. PMCID: PMC3174577.Zhao W, Blagev D, Pollack J, Erle DJ. Toward a systematic understanding of mRNA 3’untranslated regions. Proc Am Thorac Soc 8:163-6, 2011. PMCID: PMC3131834.Sugimoto K, Kudo M, Sundaram A, Ren X, Huang K, Bernstein X, Wang Y, Raymond WW,Erle DJ, Abrink M, Caughey GH, Huang X, Sheppard D. The αvβ6 integrin modulates airwayhyperresponsiveness in mice by regulating intraepithelial mast cells. J Clin Invest 122:748-58,2012. PMCID: PMC3266785.Diez D, Goto S, Fahy JV, Erle DJ, Woodruff PG, Wheelock ÅM, Wheelock CE. Networkanalysis identifies a putative role for the PPAR and type 1 interferon pathways in glucocorticoidactions in asthmatics. BMC Med Genomics 5:27, 2012. PMCID: PMC3408345.Schroeder BW, Verhaeghe C, Park SW, Nguyenvu LT, Huang X, Zhen G, Erle DJ. AGR2 isinduced in asthma and promotes allergen-induced mucin overproduction. Am J Respir Cell MolBiol 47:178-85, 2012. PMCID: PMC3423459.Solberg OD, Ostrin EJ, Love MI, Peng JC, Bhakta NR, Hou L, Nguyen C, Solon M, Nguyen C,Barczak AJ, Zlock LT, Blagev DP, Finkbeiner WE, Ansel KM, Arron JR, Erle DJ*, WoodruffPG*. Airway epithelial miRNA expression is altered in asthma. Am J Respir Crit Care Med 2012[Epub ahead of print] PubMed PMID: 22955319. * equal contributions.John Fahy, M.D.Innes AL, Wong McGrath K, Dougherty RH, McCulloch CE, Woodruff PG, Seibold MA,Okamoto KS, Kelsey J. Ingmundson KJ, Solon MC, Carrington SD, Fahy JV. The H Antigen atEpithelial Surfaces is Associated with Susceptibility to Asthma Exacerbation. Am J Respir CritCare Med. 2011;183:189-94. PMCID: PMC3040389.Choy DF, Modrek B, Abbas AR, Kummerfeld S, Clark HF, Wu LC, Fedorowicz G, Modrusan Z,Fahy JV, Woodruff PG, Arron JR. Gene expression patterns of Th2 inflammation andintercellular communication in asthmatic airways. J Immunol. 2011 Feb 1;186(3):1861-9.Fahy JV, Locksley RM. The airway epithelium as a regulator of Th2 responses in asthma.American Journal of Respiratory and Critical Care Medicine 2011;184: 390-392.Gordon ED, Sidhu SS, Wang ZE, Woodruff PG, Yuan S, Solon MC, Conway SJ, Huang X,Locksley RM, Fahy JV. A protective role for periostin and TGFb in IgE-mediated allergy andairway hyperresponsiveness. Clinical and Experimental Allergy 2012;42:144-55.Wong McGrath K, Icitovic N, Boushey HA, Lazarus SC, Sutherland, ER, Chinchilli VM, FahyJV. A large subgroup of mild moderate asthma is persistently non-eosinophilic. AmericanJournal of Respiratory and Critical Care Medicine. 2012; 185(6):612-9.Xiaozhu Huang, M.D.Masuno K, Haldar SM, Jeyaraj D, Mailloux C, Huang X, Panettieri Jr RA, Jain MK, Gerber AN.76

Expression Profiling Identifies Klf15 as a Glucocorticoid Target that Regulates AirwayHyperresponsiveness. Am J Respir Cell Mol Biol. 2011 Jan 21Kudo M, Melton AC, Chen C, Engler MB, Huang KE, Ren X, Wang Y, Bernstein X, Li JT,Atabai K, Huang X*, Sheppard D. IL-17A produced by αβ T cells drives airway hyperresponsivenessin mice and enhances mouse and human airway smooth muscle contraction. NatMed. 2012 Mar 4;18(4):547-54 (*co-authorship)Vijayanand P, Seumois G, Simpson LJ, Abdul-Wajid S, Baumjohann D, Panduro M, Huang X,Interlandi J, Djuretic IM, Brown DR, Sharpe AH, Rao A, Ansel KM. Interleukin-4 production byfollicular helper T cells requires the conserved Il4 enhancer hypersensitivity site V. Immunity.2012 Feb 24;36(2):175-87Thornton E, Looney M, Sheppard D, Locksley R, Huang X, Krummel M. Dynamics of antigencapture and presentation revealed by two-photon live imaging in the lung. J Exp Med. 2012 Jun4;209(6):1183-99Schroeder BW, Verhaeghe C, Park SW, Nguyenvu LT, Huang X, Zhen G, Erle DJ. AGR2 isInduced in Asthma and Promotes Allergen-Induced Mucin Overproduction. Am J Respir CellMol Biol. 2012 Aug;47(2):178-85Bhattacharya M, Su G, Su X, Oses-Prieto JA, Li JT, Huang X, Hernandez H, Atakilit A,Burlingame AL, Matthay MA, Sheppard D. IQGAP1 is necessary for pulmonary vascular barrierprotection in murine acute lung injury and pneumonia. Am J Physiol Lung Cell Mol Physiol.2012 Jul 1;303(1):L12-9Chun Chen, Makoto Kudo, Florentine Rutaganira, Hiromi Takano, Candace Lee, Amha Atakilit,Toshimitsu Uede, Paul Wolters, Stephen Liggett, Kevan M. Shokat, Xiaozhu Huang and DeanSheppard . Integrin α9β1 in airway smooth muscle regulates a novel brake on exaggeratedmurine and human airway narrowing. JCI 2012 Aug 1;122(8):2916-27Huang F, Zhang H, Wu M, Yang H, Kudo M, Peters CJ, Woodruff PG, Solberg OD, Donne ML,Huang X, Sheppard, Fahy JV, Wolters PJ, Hogan BL, Finkbeiner WE, Li M, Jan YN, Jan LY,Rock JR. Calcium-activated chloride channel TMEM16A modulates mucin secretion and airwaysmooth muscle contraction. Proc Natl Acad Sci USA. 2012 Oct 2;109(40):16354-9.Julia Freimuth, Frederic F. Clermont, Xiaozhu Huang, Angela De Sapio, Taku Tokuyasu, DeanSheppard, Rosemary J. Akhurst. Epistatic interactions between Tgfb1 and genetic loci, Tgfbm2and Tgfbm3, determine susceptibility to an asthmatic stimulus. Proc Natl Acad Sci USA. 2012Oct 30;109(44):18042-7Kudo M, Khalifeh Soltani SM, Sakuma SA, McKleroy W, Lee TH, Woodruff PG, Lee JW,Huang K, Chen C, Arjomandi M, Huang X, Atabai K. Mfge8 suppresses airwayhyperresponsiveness in asthma by regulating smooth muscle contraction. Proc Natl Acad SciUSA. 2013 Jan 8;110(2):660Matthew Krummel, Ph.D.Looney MR, Thornton EE, Sen D, Lamm WJ, Glenny RW, Krummel MF. 2011. StabilizedImaging of immune surveillance in the mouse lung. Nat Methods. 8(1):91-6. PMCID:PMC3076005Englehardt JE, Boldajipour B, Beemiller P, Werb Z, Pandurangi P, Sorenson C, Egelblad M,Krummel MF, Marginating dendritic cells of the tumor microenvironment cross-present tumorantigens and stably engage tumor-specific T cells. Cancer Cell. 2012 Mar 20;21(3):402-17. doi:10.1016/j.ccr.2012.01.008. PMCID: PMC3311997Thornton EE, Krummel MF, Looney, M.R. 2012. Live Imaging of the Lung. Curr ProtocCytom. Apr; Chapter 12:Unit12.28.77

Thornton EE, Looney MR, Bose O, Sen D, Sheppard D, Locksley R, Huang X, Krummel MF.2012. Spatiotemporally Separated Antigen Uptake by Alveolar Dendritic Cells and AirwayPresentation to T Cells in the Lung. J Exp Med., 209(6):1183-99.Limin Liu, Ph.D.Wei W, Yang Z, Tang CH, Liu L (2011). Targeted deletion of GSNOR in hepatocytes of micecauses nitrosative inactivation of O 6 -alkylguanine-DNA alkyltransferase and increasedsensitivity to genotoxic diethylnitrosamine. Carcinogenesis 32:973–977.Lagoda G, Xie Y, Sezen SF, Hurt KJ, Liu L, Musicki B, Burnett AL (2011). FK506Neuroprotection after Cavernous Nerve Injury is Mediated by Thioredoxin and GlutathioneRedox Systems. J Sexual Medicine 8:3325-3334.Na B, Huang ZM, Wang Q, Qi ZX, Tian YJ, Lu CC, Yu JW, Hanes MA, Sanjay Kakara S,Huanga EJ, Ou JHJ, Liu L ‡, *, and Yen TSB ‡,† (2011). Transgenic Expression of Entire HepatitisB Virus in Mice Induces Hepatocarcinogenesis Independent of Chronic Liver Injury. PLoS One6:e26240.‡ co-senior author; *Corresponding author; † Deceased August 31, 2009.Khan O, Headley M, Gerard A, Wei W, Liu L, Krummel MF (2011). Regulation of T cellpriming by lymphoid-stromal inducible nitric oxidesynthase. PLoS ONE 6:e26138.Tang CH, Wei W, Liu L (2011). Regulation of DNA Repair by S-Nitrosylation. Biochimica etBiophysica Acta (In press; Published online: http://dx.doi.org/10.1016/j.bbagen.2011.04.014).Tang CH, Wei W, Liu L (2012). Regulation of DNA Repair by S-Nitrosylation. Biochim BiophysActa 1820:730–735 (PMC3170507; http://dx.doi.org/10.1016/j.bbagen.2011.04.014).Ozawa K*, Tsumoto H, Wei W, Tang CH, Komatsubara AT, Kawafune H, Shimizu K, Liu L*,Tsujimoto G (2012). Proteomic analysis of the role of S-nitrosoglutathione reductase inlipopolysaccharide-challenged mice. Proteomics 12, 2024-2035. *Corresponding author.Leung J, Wei W, Liu L (2013). S-nitrosoglutathione reductase deficiency increases mutagenesisfrom alkylation in mouse liver. Carcinogenesis (in press).Richard Locksley, M.D.Wu D, AB Molofsky, HE Liang, RR Ricardo-Gonzalez, HA Jouihan, JK Bando, A Chawla, RMLocksley. 2011. Eosinophils sustain adipose alternatively activated macrophages associatedwith glucose homeostasis. Science 332:243-247.Sullivan BM, H-E Liang, JK Bando, D Wu, LE Cheng, JK McKerrow, CDC Allen, RMLocksley. 2011. Genetic analysis of basophil function in vivo. Nature Immunol 12:527-535.Nguyen KD, Y Qui, X Cui, YP Sharon Goh, J Mwangi, T David, L Mukundan, F Brombacher,RM Locksley, A Chawla. 2011. Alternatively activated macrophages produce catecholaminesto sustain adaptive thermogenesis. Nature 480:104-108.Liang H-E, RL Reinhardt, JK Bando, BM Sullivan, I-C Ho, RM Locksley. 2011. Divergentexpression patterns of IL-4 and IL-13 define unique functions in allergic immunity. NatureImmunol 13:58-66.Dickgreber N, KJ Farrand, N van Panhuys, DA Knight, ML Chong, S Miranda-Hernandez, AGBaxter, RM Locksley, G Le Gros, IF Hermans. 2012. Immature murine NKT cells passthrough a stage of developmentally programmed innate IL-4 secretion. J Leukoc Biol (in press)Gordon E, S Sidhu, Z-E Wang, P Woodruff, S Yuan, M Solon, S Conway, X Huang, RMLocksley, J Fahy. 2012. A protective role for periostin and TGF-b in IgE-mediated allergy andairway hyperresponsiveness. Clin Exp Allergy 42:144-155. PMC327179278

Thornton EE, MR Looney, O Bose, D Sen, D Sheppard, RM Locksley, X Huang, MF Krummel.2012. Spatiotemporally separated antigen uptake by alveolar dendritic cells and airwaypresentation to T cells in the lung. J Exp Med 209:1183-1199. PMC3371730Price AE, RL Reinhardt, H-E Liang, RM Locksley. 2012. Marking and quantifying IL-17Aproducingcells in vivo. PLoS ONE 7:e39750. PMC3387253Cheng LE, K Hartmann, A Roers, MF Krummel, RM Locksley. 2013. Perivascular mast cellsdynamically probe cutaneous blood vessels to capture IgE. Immunity 38:166-175. PMC inprocessOghumu S, R Dong, S Varikuti, T Shawler, T Kampfrath, CA Terrazas, C Lezama-Davila,BMM Ahmer, CC Whitacre, S Rajagopalan, R Locksley, AH Sharpe, AR Sataskar. 2013.Distinct populations of innate CD8 T cells revealed in a CXCR3 reporter mouse. J Immunol (inpress).Molofsky AB, JC Nussbaum H-E Liang, SJ Van Dyken, LE Cheng, A Mohapatra, A Chawla,RM Locksley. 2013. Innate lymphoid type 2 cells ILC2) sustain visceral adipose tissueeosinophils and alternatively activated macrophages. J Exp Med (in press). PMC in processVan Dyken SJ, RM Locksley. 2013. Interleukin-4- and interleukin-13-mediated alternativelyactivated macrophages: roles in homeostasis and disease. Annu Rev Immunol 31:317-43. PMCin processSpits H, D Artis, M Colonna, A Diefenbach, JP Di Santo, G Eberl, S Koyasu, RM Locksley,ANJ McKenzie, RE Mebius, F Powrie, E Vivier. 2013. Innate lymphoid cells – a proposal for auniform nomenclature. Nature Rev Immunol 13:145-149. PMC in processHeredia JE, L mukundan, FM Chen, AA Mueller, R Deo, RM Locksley, TA Radno, A Chawla.2013. Type 2 innate signals regulate functionality of fibro/adipogenic progenitors to facilitatemuscle regeneration. Cell (in press).William Seaman, M.D.Rebres, RA, Roach TIA, Fraser IDC, Philip F, Moon C, Lin KM, Liu J, Santat L, Cheadle L,Ross EM, Simon MI, Seaman WE: Synergistic Ca2+ responses by Gai- and Gaq-coupled G-protein-coupled receptors require a single PLCb isoform that is sensitive to both Gbg and Gaq. JBiol Chem 286:1-10, 2011Dean Sheppard, M.D.Spassov DS, Wong CH, Sergina N, Ahuja D, Fried M, Sheppard D, Moasser MM. A src-drivenphosphotyrosine signaling switch determines the anchorage state of epithelial cells. Mol CellBiol 2011 31:776-82. PMCID: PMC3028653Su G, Atakilit A, Li T. J, Wu N, Bhattacharya M, Zhu J, Li E, Sun S, Chen R, Su C, SheppardD. Integrin αvβ3 prevents vascular leak in mice by regulating cortical actin formation inendothelial cells. Am J Resp Crit Care Med 2012 (in press)Kudo M, Melton AC, Chen C, Engler M, Huang KE, Ren X, Wang Y, Bernstein X, Li J, AtabaiK, Huang X, Sheppard D. IL-17A produced by ab T cells drives airway smooth musclecontraction. Nature Medicine 2012 (in press).Sugimoto K, Kudo M, Sundaram A, Ren X, Huang K, Bernstein X, Wang Y, Raymond WW,Erle D, Abrink M, Caughey GH, Huang X, Sheppard D. The avb6 integrin modulates airwayhyperresponsiveness by regulating intra-epithelial mast cells. J Clin Invest 2012 (in press).Su G, Atakilit A, Li T. J, Wu N, Bhattacharya M, Zhu J, Li E, Sun S, Chen R, Su C, SheppardD. Integrin αvβ3 prevents vascular leak in mice by regulating cortical actin formation inendothelial cells. Am J Resp Crit Care Med 2012 (in press)79

Giacomini M, Travis M, Sheppard D. Epithelial cells utilize cortical actin/myosin to activatelatent TGF-β through integrin αvβ6-dependent physical force. Exp Cell Res 2012 318:716-22.PMID: 22309779.Chen C, Kudo M, Rutaganira F, Takano H, Lee C, Atakilit A, Robinett, KS, Uede T, Wolters P,Shokat KM, Huang X, Sheppard D. Integrin alpha9beta1 in airway smooth muscle regulates anovel brake on exaggerated murine and human airway narrowing J Clin Invest 2012 122:2916-27 PMID 22772469.Bhattacharya M, Su G, Su X, Oses-Prieto JA, Li JT, Huang X, Hernandez H, Atakilit A,Burlingame AL, Matthay M, Sheppard D. IQGAP1 is necessary for pulmonary vascular barrierprotection in murine acute lung injury and pneumonia Am J Physiol: Lung Cell and Mol Biol2012 303:L12-19 PMID: 22561460.Jeoung-Sook ShinBaravalle, G, Park, H, McSweeney, M, Ohmura-Hoshino, M, Matsuki, Y, Shin, JS.Ubiquitination of CD86 is a key mechanism in regulating antigen presentation by dendritic cells,J Immunology. 187:2966, 2011Ma JK, Platt MY, Eastham-Anderson J, Shin JS*, and Mellman I*. MHC class II distribution indendritic cells and B cells is determined by ubiquitin chain length, PNAS. 2012 May 7 [Epubahead of print]Zhi-En Wang, M.D., M.S.Gordon E, S Sidhu, Z-E Wang, P Woodruff, S Yuan, M Solonm S Conway, X Huang, RMLocksley, J Fahy. 2012. A protective role for periostin and TGF-b in IgE-mediated allergy andairway hyperresponsiveness. Clin Exp Allergy 42: 144-155. PMC3271792Arthur Weiss, M.D., Ph.D.Limnander A, Depeille P, Freedman TS, Liou J, Leitges M, Kurosaki T, Roose JP, and Weiss A.Stim1, PKCd, and RasGRP proteins set a threshold for pro-apoptotic Erk signaling during B celldevelopment. Nat. Immunol., 12:425-433. 2011. PMID: 21441934Zhu JW, Doan K, Park J, Chau AH, Zhang H, Lowell CA and Weiss A. Distinct functions ofreceptor-like tyrosine phosphatases CD45 and CD148 in chemoattractant-mediated neutrophilmigration and response to S. aureus infection. Immunity. 35:757-769. 2011. PMID: 22078799Zikherman J, Doan K, Parameswaran R, Raschke W, and Weiss A. Quantitative differences inCD45 expression unmask functions for CD45 in B-cell development, tolerance and survival.Proc. Natl. Acad. Sci. USA. ePub ahead of print. 2011. PMID: 22135465Mukherjee S, Zhu J, Zikherman J, Parameswaran R, Kadlecek TA, Wang Q, Au-Yeung B,Ploegh H, Kuriyan J, Das J*, and Weiss A* Monovalent and multivalent ligation of the B cellreceptor exhibit differential dependence upon Syk and Src family kinases. Sci. Signal. 2013.Jan 1;6(256):ra1 PMID: 23281368 *co-corresponding authorsZikherman J, Parameswaran R, Hermiston M, and Weiss A. The wedge domain of the receptorliketyrosine phosphatase CD45 enforces B cell tolerance by regulating substrate specificity. J.Immunol., in press. 2013.Jonathan Weissman, Ph.D.Churchman LS, Weissman JS. (2011) Nascent transcript sequencing visualizes transcription atnucleotide resolution. Nature, 469: 368-73. PMID 2124884480

Ingolia NT, Lareau LF, Weissman JS. (2011) Ribosome profiling of mouse embryonic stemcells reveals the complexity and dynamics of Mammalian proteomes. Cell, 147: 789-802.PMC3225288Oh E, Becker AH, Sandikci A, Huber D, Chaba R, Gloge F, Nichols RJ, Typas A, Gross CA,Kramer G, Weissman JS, Bukau B. (2011) Selective ribosome profiling reveals the cotranslationalchaperone action of trigger factor in vivo. Cell, 147: 1295-1308. PMID: 22153074Brar GA, Yassour M, Friedman N, Regev A, Ingolia NT, Weissman JS. (2012) High-resolutionview of the yeast meiotic program revealed by ribosome profiling. Science, 335: 552-7. PMID22194413Li GW, Oh E, Weissman JS. (2012) The anti-Shine-Dalgamo sequence drives translationalpausing and codon choice in bacteria. Nature, 484: 538-41. PMC3338875Ingolia NT, Brar GA, Rouskin S, McGeachy AM, Weissman JS. (2012) The ribosome profilingstrategy for monitoring translation in vivo by deep sequencing of ribosome-protected mRNAfragments. Nature Protocols, 7: 1534-50. PMID 22836135Carvunis AR, Rolland T, Wapinski I, Calderwood MA, Yildirim MA, Simonis N, CharloteauxB, Hidalgo CA, Barbette J, Santhanam B, Brar GA, Weissman JS, Regev A, Thierry-Mieg N,Cusick ME, Vidal M. (2012) Proto-genes and de novo gene birth. Nature, 487: 370-4.PMC3401362Brandman O, Stewart-Ornstein J, Wong D, Larson A, Williams CC, Li GW, Zhou S, King D,Shen PS, Weibezahn J, Dunn JG, Rouskin S, Inada T, Frost A, Weissman JS. (2012) Aribosome-bound quality control complex triggers degradation of nascent peptides and signalstranslation stress. Cell, 151: 1042-54. PMID 23178123Stern-Ginossar N, Weisburd B, Michalski A, Le VT, Hein MY, Huang SX, Ma M, Shen B, QianSB, Hengel H, Mann M, Ingolia NT, Weissman JS. (2012) Decoding human cytomegalovirus.Science, 338: 1088-93. PMID 23180859Zena Werb, M.D.Hong JS, KJ Greenlee, R Pitchumani, S-H Lee, L-z Song, M Shan, SH Chang, PW Park, CDong, Z Werb, A Bidani, DB Corry & F Kheradmand (2011). Dual protective mechanisms ofmatrix metalloproteinases 2 and 9 in immune defense against Streptococcus pneumoniae. J.Immunol. 186:6427-6436. [2011 Apr 20, Epub ahead of print]. PMID: 21508260.Lemieux GA., J Liu, N Mayer, RJ Bainton, K Ashrafi & Z Werb (2011). A whole-organismscreen identifies new regulators of fat storage. Nature Chem. Biol. 7: 206-213. [Mar 13. Epubahead of print]. PMID: 21390037; PMCID: PMC3076723.Phillips JJ, A Ward, E Huillard, A Robinson, DH Lum, M-Y Polley, SD Rosen, DH Rowitch &Z Werb (2012). Heparan sulfate sulfatase SULF2 regulates PDGFRa signaling and growth inmalignant glioblastoma. J. Clin. Invest. In press.Engelhardt JE, B Boldajipour, P Beemiller, P Pandurangi, C Sorenson, Z Werb, M Egeblad &MF Krummel. (2011). Marginating dendritic cells of the tumor microenvironment cross-presentantigens and stably engage tumor-specific T cells. Cancer Cell. In press.Slorach EM, J Chou & Z Werb (2011). Zeppo1 is a novel metastasis promoter that represses E-cadherin expression and regulates p120-catenin isoform expression and localization. Genes Dev.25: 471-484. [Epub ahead of print February 11, 2011]. PMCID: PMC3049288.Caudrillier A, K Kessenbrock, BM Gilliss, JX Nguyen, MB Marques, M Monestier, P Toy, ZWerb & MR Looney (2012). Platelets induce neutrophil extracellular traps in transfusion-relatedacute lung injury. J. Clin. Invest. 122(7):2661–2671. [Epub ahead of print, Jun 11]. PMID:81

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Eri1 regulates microRNA homeostasis and mouse lymphocyte development and antiviralfunction. Thomas MF, Abdul-Wajid S, Panduro M, Babiarz JE, Rajaram M, Woodruff P, LanierLL, Heissmeyer V, Ansel KM. Blood. 2012 Jul 5;120(1):130-42. Epub 2012 May 21.Jia G, Erickson RW, Choy DF, Mosesova S, Wu LC, Solberg OD, Shikotra A, Carter R,Audusseau S, Hamid Q, Bradding P, Fahy JV, Woodruff PG, Harris JM, Arron JR;Bronchoscopic Exploratory Research Study of Biomarkers in Corticosteroid-refractory Asthma(BOBCAT) Study Group. Periostin is a systemic biomarker of eosinophilic airway inflammationin asthmatic patients. J Allergy Clin Immunol. 2012 Sep;130(3):647-654Solberg OD, Ostrin EJ, Love MI, Peng JC, Bhakta NR, Hou L, Nguyen C, Solon M, Nguyen C,Barczak AJ, Zlock LT, Blagev DP, Finkbeiner WE, Ansel KM, Arron JR, Erle DJ, WoodruffPG. Airway Epithelial miRNA Expression is Altered in Asthma. Am J Respir Crit Care Med.2012 Sep 6. [Epub ahead of print]Huang F, Zhang H, Wu M, Yang H, Kudo M, Peters CJ, Woodruff PG, Solberg OD, DonneML, Huang X, Sheppard D, Fahy JV, Wolters PJ, Hogan BL, Finkbeiner WE, Li M, Jan YN, JanLY, Rock JR. Calcium-activated chloride channel TMEM16A modulates mucin secretion andairway smooth muscle contraction. Proc Natl Acad Sci USA. 2012 Sep 17. [Epub ahead of print]83

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Looking to the FutureRichard M. Locksley, M.D.The SABRE Center is evolving into a more mature entity. All but one of the recruitedfaculty/fellow has obtained R01 NIH funding (the one exception has re-submitted with avery close score and received bridge funding from the School of Medicine based onpromise of future success), the first recruit has been promoted to Associate Professor andthe second, Mark Ansel, was just put up for promotion this summer. The Fellow, Dr.Allen, was recruited to the faculty at the Cardiovascular Research Institute at MissionBay and will begin to anchor asthma-related research at that site. The first postdocs andgraduate students have left to assume positions after training in the SABRE Center. TheSABRE Center is recognized nationally by virtue of participation in each of the majorasthma multi-institutional efforts of the NIH, including as a member of AsthmaNet(under the leadership of Homer Boushey), the Severe Asthma Research Program (SARP;under the leadership of John Fahy) and the Asthma and Allergic Diseases CooperativeResearch Center Network (under the leadership of Dean Sheppard). Members of theSABRE Center were awarded a Program Project Grant to investigate the role of innatelymphoid cells in human asthma (Fahy, Locksley, Ansel, Woodruff). Extramural fundingbrought in solely by the 5 core basic investigators has more than doubled over the past 5years; the totals accrued to the entire program have been leveraged to an even greaterextent. The conferences and seminars are well attended and publicized. Thus, by anumber of metrics, asthma-centered research is now well established and recognized atUCSF.Given the current political climate, it is likely that continued government support forhealth sciences will be capped or decline, such that unlimited growth from this sector willnot be possible. Although we continue to compete aggressively in this arena, prioritizingresearch dollars from the Foundation will become increasingly important. Highlysuccessful focused research models from the past, such as Bell Laboratories or theCavendish laboratory at Cambridge University, reveal several commonalities, includingsmall laboratories with a shared research goal; technological innovation; and an ability tochange directions quickly to follow-up new insights. Some of these aspects we share, butre-evaluating our strategies will be an important component for moving forwardsuccessfully. Ultimately, the SABRE Center will need to move more comprehensively tostudies on human patients utilizing human tissues; will need to capture more individualslike Chris Allen early in science when they can be attracted into the field in a lasting andsubstantive way; will need to move seamlessly into ‘big science’ technologically-drivenfields at low cost, necessitating an interactive and integrated group of scientists; will needto partner with industry in ways to move scientific understanding towards interventionalefforts that remain cost-prohibitive for a small Center; and will need to grow an endowedfinancial base that will enable nimble re-direction and follow-up using competitivepriorities to fund shifting emergent needs for equipment, personnel (including visitingscientists) and short-term needs in response to windows of opportunity. Funding fixedCores may not be an optimal resource allocation, as technology advances, cores becomeincreasingly mainstreamed and publicly available, and costs continue to decrease. Inshort, with the help of both the Executive Board and the Scientific Advisory Board, the90

SABRE Center will work to develop a Strategic Plan in order to shape the research andfinancial priorities for the coming decade. Our hope is to continue the trajectoryestablished by the last 5 years on a pathway of increasing success in our mission tounderstand and ultimately conquer asthma. These challenges we take seriously for thefuture in order to honor the extraordinary vision of the Sandler family in committingresources to asthma basic research at UCSF. We are most grateful for the opportunity torespond to the challenge and look forward to discoveries that will impact thisincreasingly prevalent disease of humans.91

Sandler Asthma Basic REsearch CenterBiographical sketchesBIOGRAPHICAL SKETCHES92

BIOGRAPHICAL SKETCHESChristopher Allen, Ph.D.K. Mark Ansel, Ph.D.Homer Boushey, M.D.Esteban Burchard, M.D., M.P.H.George Caughey, M.D.Harold Chapman, M.D.Anthony DeFranco, Ph.D.David Erle, M.D.John Fahy, M.D., M.Sc.Xiaozhu Huang, M.D., M.S.Matthew Krummel, Ph.D.Limin Liu, Ph.D.Richard Locksley, M.D.William Seaman, M.D.Dean Sheppard, M.D.Jeoung-Sook Shin, Ph.DZhi-En Wang, M.D., M.S.Arthur Weiss, M.D., Ph.D.Jonathan Weissman, PhD.Zena Werb, PhD.Prescott Woodruff, M.D., M.P.H.93

BIOGRAPHICAL SKETCHNAMEChristopher David Caballero Allen, Ph.D.POSITION TITLESandler-Newmann Foundation UCSF Fellow inAsthma ResearchEDUCATION/TRAININGINSTITUTION AND LOCATION DEGREE YEAR(s) FIELD OF STUDYMassachusetts Institute of Technology B.S. 2001 BiologyUniversity of California, San Francisco Ph.D. 2007 BiomedicalUniversity of California, San Francisco Postdoctoral 2007 Sciences ImmunologyaralralPositions and Honors1998-2000 Summer Research Intern, Department of Molecular and CellularPharmacology, Isis Pharmaceuticals, Carlsbad, CA2000 Undergraduate Student Researcher, Laboratory of Herman Eisen, Centerfor Cancer Research, Massachusetts Institute of Technology2001-2007 Graduate Student Researcher, Laboratory of Jason Cyster, BiomedicalSciences Graduate Program and Immunology Graduate Program,University of California, San Francisco, CA2007 Postdoctoral Scholar, Laboratory of Jason Cyster, Department ofMicrobiology and Immunology, University of California, San Francisco2007–2012 Sandler-Newmann Foundation UCSF Fellow in Asthma Research, SandlerAsthma Basic Research Center and the Department of Microbiology andImmunology, University of California, San Francisco, CA2012 – Present Assistant Professor Cardiovascular Research Institute, Department ofAnatomy and Department of Microbiology and Immunology, SandlerAsthma Basic Research Center, University of California, San Francisco1994-1995 National Science Foundation Young Scholars Program Fellowship1997 National Hispanic Scholar1998 San Diego Biotech Employee Development Coalition (BEDC)Scholarship1999, 2000 Academic Excellence Award, Office of Minority Education,Massachusetts Institute of Technology2001 Phi Beta Kappa2001 Whitehead Prize in Biomedical Research2001–2002 University of California Regents Fellowship94

2002–2007 Howard Hughes Medical Institute Predoctoral Fellowship2010 Seminars in Immunology Top Cited Article 2008-20102012 NIH Director’s New Innovator AwardSelected peer-reviewed publications (in chronological order)1. Allen C.D.C., Ansel K.M., Low C., Lesley R., Tamamura H., Fujii N. Cyster J.G. (2004).Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5.Nature Immunology, 5(9), 943-952.2. Chen T.T., Li L., Chung D.H., Allen C.D.C., Torti S.V., Torti F.M., Cyster J.G., Chen C.Y.,Brodsky F.M., Niemi E.C., Nakamura M.C., Seaman W.E., Daws M.R. (2005). TIM-2 isexpressed on B cells and in liver and kidney and is a receptor for H-ferritin endocytosis. TheJournal of Experimental Medicine, 202(7), 955-965. PMC2213179.3. Allen C.D.C., Okada T., Tang H.L., Cyster J.G. (2007). Imaging of germinal center selectionevents during affinity maturation. Science, 315(5811), 528-531.4. *Allen C.D.C., *Okada T., *Cyster J.G. (2007). Germinal-center organization and cellulardynamics. Immunity 27(2), 190-202. *co-corresponding author. PMCID: PMC2242846.5. Haynes N.M., Allen C.D.C., Lesley R., Ansel K.M., Killeen N., and Cyster J.G. (2007). Roleof CXCR5 and CCR7 in follicular Th cell positioning and appearance of a programmed celldeath gene-1 High germinal center-associated subpopulation. The Journal of Immunology,179(8), 5099-5108.6. *Allen C.D.C., *Cyster J.G. (2008). Follicular dendritic cell networks of primary folliclesand germinal centers: phenotype and function. Seminars in Immunology 20(1), 14-25. *cocorrespondingauthor PMCID: PMC2366796.7. Sullivan B.M., Liang H.E., Bando J.K., Wu D., Cheng L.E., McKerrow J.K., *Allen C.D.C.,*Locksley R.M. (2011). Genetic analysis of basophil function in vivo. Nature Immunology,12(6), 527-535. *co-corresponding author. PMCID: 3271435.8. Beltman J.B., Allen C.D.C., Cyster J.G., de Boer R.J. (2011). B cells within germinal centersmigrate preferentially from dark to light zone. Proceedings of the National Academy ofSciences, 108(21), 8755-8760. PMCID: PMC3102384.9. Green J.A., Suzuki K., Cho B., Willison L.D., Palmer D., Allen C.D.C., Schmidt T.H., XuY., Proia R.L., Coughlin S.R., Cyster J.G. (2011). The sphingosine 1-phosphate receptorS1P 2 maintains the homeostasis of germinal center B cells and promotes niche confinement.Nature Immunology, 12(7), 672-680. PMCID: PMC3158008.10. Steiner D.F., Thomas M.F., Hu J.K., Yang Z., Babiarz J.E., Allen C.D.C., Matloubian M.,Blelloch R., Ansel K.M. (2011). MicroRNA-29 Regulates T-Box Transcription Factors andInterferon-γ Production in Helper T Cells. Immunity, 35(2), 169-181. PMCD: PMC3361370.11. Yang Z., Sullivan B.M., Allen C.D.C. (2012). Fluorescent in vivo detection reveals that IgE +B cells are restrained by an intrinsic cell fate predisposition. Immunity, 36(5), 857-872.95

Research SupportOngoing Research Support1 DP2 HL117752-01 Allen (PI) 09/30/2012 – 08/31/2017NIH/NHLBICellular interactions in asthmaThis project is focused on the dynamic communication among inflammatory cells inasthmatic lungs. The major goals of this project are to develop technical approaches tosimultaneously visualize multiple different types of inflammatory cells in the lung, followedby characterization of relevant cellular interactions in a combinatorial fashion, and thendefinition of the stromal microenvironments in which these interactions occur.Role: PI1 R01 AI103146-01 Allen (PI) 12/01/2012 – 11/30/2017NIH/NIAIDAnalysis of basophil function in secondary immune responsesThe major goal of this project is to determine the functional role of basophils that havecaptured antigen via IgE antibodies in secondary immune responses. Specifically, this projectwill determine whether basophils contribute to antigen transport, to the enhancement ofadaptive immunity, and to tissue damage and repair.Role: PICompleted Research SupportNone96

BIOGRAPHICAL SKETCHNAMEK. Mark AnseleRA COMMONS USER NAMEanselmPOSITION TITLEAssistant Professor of Microbiology andImmunologyEDUCATION/TRAININGINSTITUTION AND LOCATION DEGREE YEAR(s) FIELD OF STUDYVirginia Tech (Blacksburg, VA) B.S. 1992-1996 BiochemistryUniversity of California, San Francisco Ph.D. 1996-2001 Biomedical SciencesImmune Disease Institute, Harvard Medical School 2001-2007 ImmunologyPositions2001 – 2005 Postdoctoral Fellow, Immune Disease Institute (p.k.a. Center for BloodResearch), Harvard Medical School, Boston, MA2005 – 2007 Instructor, Department of Pediatrics, Children’s Hospital and ImmuneDisease Institute (p.k.a. Center for Blood Research), Harvard MedicalSchool, Boston, MA2008 – Present Assistant Professor, Department of Microbiology and Immunology andSandler Asthma Basic Research Center, University of California SanFranciscoOther Experience and Professional Memberships1998 - American Association for the Advancement of Science2006 - American Association of Immunologists2007 - International Cytokine Society2011 - Board of Reviewing Editors, Science Signaling2011 - International Predoctoral Fellows Review Cmte.,Howard Hughes Medical Institute2012 - NIH peer review committee: Cellular & MolecularImmunology B, ad hoc reviewerAwards and Honors1997 – 2001 Howard Hughes Medical Institute Predoctoral Fellowship2001 – 2004 Damon Runyon Cancer Research Fund Postdoctoral Fellowship2005 – 2007 Leukemia and Lymphoma Society Special Fellow2006 Burroughs Wellcome Career Award in Biomedical Sciences97

2007 International Cytokine Society Outstanding Postdoctoral Fellow2009 Dana Foundation Human Immunology Scholar2012 American Association of Immunologists Young Investigator TravelAward2012 Leukemia & Lymphoma Society ScholarSelected Peer-reviewed Publications1. Grégory Seumois, Pandurangan Vijayanand, Christopher J Eisley, Nada Omran, LukasKalinke, Mai North, Asha P. Ganesan, Laura J Simpson, Nathan Hunkapiller, FleixMolzahan, Prescott G Woodruff, John V Fahy, David J Erle, Ratka Djukanovic, RobertBlelloch, K Mark Ansel: An integrated nano-scale approach to profile miRNAs in limitedclinical samples. Am J Clin Exp Immuol. 1:70-89 (2012)2. Hoefig KP, Rath N, Heinz GA, Wolf C, Dameris J, Schepers A, Kremmer E, Ansel KM,Heissmeyer V. Eri1 degrades the stem-loop of oligouridylated histone mRNAs to inducereplication-dependent decay. Nat Struct Mol Biol. 20:73-81 (2013)3. Solberg OD, Ostrin EJ, Love MI, Peng JC, Bhakta NR, Hou L, Nguyen C, Solon M, NguyenC, Barczak AJ, Zlock LT, Blaev DP, Finkbeiner WE, Ansel KM, Arron JR, Erle DJ,Woodruff PG. Airway Epithelial miRNA Expression is Altered in Asthma. Am. J. Respir.Crit. Care Med. 186:965-74 (2012)4. Thomas MF, Abdul-Wajid S, Panduro M, Babiarz JE, Rajaram M, Woodruff P, Lanier LL,Heissmeyer , Ansel KM. Eri1 regulates microRNA homeostasis and mouse lymphocytedevelopment and anti-viral fuction. Blood. 120:130-42 (2012)5. Vijayanand P, Seumois G, Simpson LJ, Abdual-Wajid S, Baumjohann D, Panduro M, HuangX, Interlandi J, Djuretic IM, Brown DR, Sharpe AH, Rao A, Ansel KM. Interleukin-4Productio y Follicular Helper T Cells Requires the Conserved Il4 Enhancer HypersensitivitySite V. Immunity 36:175-87 (2012)6. Baumjohann D, Okada T, Ansel KM. Cutting Edge: Distinct Waves of BCL6 Expressionduring T Follicular Helper Cell Development. J Immunol.187: 2089-92 (2011)7. Steiner DF, Thomas MF, Hu JK, Yang Z, Babiarz JE, Allen CD, Matloubian M, Blelloch R,Ansel KM. MicroRNA-29 Regulates T-Box Transcription Factors and Interferon-γProduction in Helper T Cells. Immunity 35:169-81 (2011)8. Sofi MH, Qiao Y, Ansel KM, Kubo M, Chang CH. Induction and Maintenance of IL-4Expression Are Regulated Differently by the 3' Enhancer in CD4 T Cells. J. Immunol.186:2792-9 (2011)9. Thomas MF, Ansel KM. Construction of small RNA cDNA libraries for deep sequencing.Methods Mol Biol. 667:93-111 (2010)10. Parameswaran P, Sklan E, Wilkins C, Burgon T, Samuel MA, Lu R, Ansel KM, HeissmeyerV, Einav S, Jackson W, Doukas T, Paranjape S, Polacek C, Barreto dos Santos F, Jalili R,Babrzadeh F, Gharizadeh B, Grimm D, Kay M, Koike S, Sarnow P, Ronaghi M, Ding SW,Harris E, Chow M, Diamond MS, Kirkegaard K, Glenn JS, Fire AZ. Six RNA Viruses andForty-One Hosts: Viral Small RNAs and Modulation of Small RNA Repertoires inVertebrate and Invertebrate Systems. PLoS Pathog. 6:e1000764 (2010)98

11. Ansel KM # , Pastor WA, Rath N, Lapan AD, Glasmacher E, Wolf C, Smith LC,Papadopoulou N, Lamperti E, Tahiliani M, Ellwart JW, Shi Y, Kremmer E, Rao A,Heissmeyer V # . Mouse ERI-1 interacts with the ribosome and catalyzes 5.8S rRNAprocessing. Nat. Struct. Mol. Biol. 15:523-30 (2008) ( # corresponding authors, equalcontribution)12. Haynes NM, Allen CD, Lesley R, Ansel KM, Killeen N, Cyster JG. Role of CXCR5 andCCR7 in Follicular Th Cell Positioning and Appearance of a Programmed Cell Death Gene 1High Germinal Center-Associated Subpopulation. J. Immunol. 179:5099-108 (2007)13. Thai TH, Calado DP, Casola S, Ansel KM, Xiao C, Xue Y, Murphy A, Frendewey D,Valenzuela D, Kutok JL, Schmidt-Supprian M, Rajewsky N, Yancopoulos G, Rao A,Rajewsky K. Regulation of the germinal center response by microRNA-155. Science316:604-8 (2007)14. Djuretic IM, Levanon D, Negreanu V, Groner Y, Rao A, Ansel KM. T-bet and Runx3cooperate to activate Ifng and silence Il4 in Th1 cells. Nat. Immunol. 8:145-53 (2007)15. Ansel KM, Djuretic I, Tanasa B, Rao A. Regulation of Th2 differentiation and the IL4 locus.Annu. Rev. Immunol. 24:607-56 (2006)16. Bronevetsky Y, Villarino AV, Eisley C, Barbeau R, Barczak A, Heinz GA, Kremmer E,Heissmeyer V, McManus MT, Erle DJ, Rao A, Ansel KM. T cell activation inducesproteasomal degradation of Argonaute and rapid remodeling of the micro RNA repertoire. J.Exp. Med., in press.17. Baumjohann D, Clingan JM, de Kouchkovsky D, Bannard O, Bluestone JA, Matloubian M,Ansel KM#, Jeker LT#. The microRNA cluster miR-17-92 is essential for follicular helperT cell differentiation. Under revision at Nature Immunology (#co-corresponding authors).Research SupportOngoing Research Support1PO1HL107202 Fahy (PI) 8/15/12 – 5-31-17NIH/NHLBIInnate and adaptive immune responses in Th2-high asthma (PI Dr. John Fahy, co-directorUCSF ACRC) Project 2: Role of miRNAs in Th2-Driven inflammation in Asthma (ProjectLeader Ansel) Project 3: Mechanisms of airway Th2 inflammation in asthma (Project LeaderFahy, Co- project Leader, Ansel). The major goal of this PPG is to elucidate cellular andmolecular mechanisms underlying the initiation and maintenance of Th2-high asthma. Thegoals of Project 2 are to identify miRNAs that regulate helper T cell functions relevant toasthma, to discover asthma associated T cell miRNA expression patterns in clinical samples,and to determine the mRNA targets and in vivo role of miR-29 in mouse model of asthma. Myrole in aim 3 is immunophenotyping of innate helper type II cells in human asthma.Role: Project 2 Leader, Project 3 co-project leader1R01HL109102-01 Ansel (PI) 8/1/11 – 6/30/16NIH/NHLBIRole of miRNAs in Th2-driven inflammation in asthma99

The major goals of this project are to discover asthma-associated T cell miRNA expressionpatterns in clinical samples, and to identify and characterize the in vivo activity of miRNAs thatregulate helper T cell functions relevant to asthma. The project will be conducted incollaboration with co-investigator Dr. Prescott Woodruff, co-director of the UCSF AirwayClinical Research Center.LLS Scholar Award Ansel (PI) 7/1/12 – 6/30/17Leukemia & Lymphoma SocietyMicroRNA regulation of lymphocyte growth and effector functionsThis career development program award would support our research program focus onmiRNAs that regulate essential helper T cell functions that contribute to immunity,immunopathology, and immune malignancies. In particular, we aim to identify andcharacterize miRNAs that regulate helper T cell growth, survival, and cytokine production.Pending Research Support1R21AI105270 Ansel (PI) 7/1/13 – 6/30/15NIH/NIAIDMolecular mechanisms of Eri1 regulation of antiviral immunityThe major goals of this project is to elucidate the molecular mechanisms by which theexoribonuclease Eri1 controls antiviral immune responses mediated by T and NK lymphocytes.Genetic and biochemical approaches will be used to determine the contribution of direct effectson mRNA stability and translation and the indirect effects of Eri1 regulation of microRNAhomeostasis.Role: PI1U19 CA179512 Blelloch (PI) 7/1/13 – 6/30/18NIH/Director’s OfficeIn Vivo Regulated Release and Function of Extracellular Small RNAsThis U19 Center’s long-term goal is to uncover paradigms of extracellular small RNA functionin health and disease and apply those paradigms to clinically relevant settings includingbiomarker discovery and therapeutic intervention. As leader of Project 1, I will conduct studiesto test the central hypothesis that immune cells release ex-miRNAs in response to inflammatorystimuli, and that this process is critical for their immune function.Completed Research Support1R56AI089828-01 Ansel (PI) 9/1/10 – 7/31/11NIH/NHLBIRegulation of miRNA expression during helper T cell differentiationThe goal of these studies is to dissect the mechanisms that govern changes in miRNAexpression during the activation of T lymphocytes, and to define how the global regulation ofmiRNA homeostasis affects T cell activation and immune function.100

Human Immunology Scholars Program Ansel (PI) 2/1/09 – 1/31/12Dana FoundationMicroRNA regulation of helper T cell function in asthmaThe major goals of this proposal are to optimize technology for miRNA profiling by qPCR andperform a pilot study of miRNA expression in a small set of clinical samples, to develop alentiviral miRNA expression library for studies of miRNA function in T cells, and to developsystems for miRNA inhibitor testing in lung explants.101

BIOGRAPHICAL SKETCHNAMEHomer A. Boushey, Jr., M.D.eRA COMMONS USER NAMEBousheyPOSITION TITLEProfessor of MedicineEDUCATION/TRAININGINSTITUTION AND LOCATION DEGREE YEAR(s) FIELD OF STUDYStanford University, Palo Alto, CA A.B. 1964 BiologyUniversity of California, San Fancisco, CA M.D. 1968 MedicineUniversity of California, San Francisco, CA Reside 1970 Internal MedicineBeth Israel Hospital, Boston, MAncy Reside 1971 Internal MedicineOxford University, Oxford, Englandncy Fellow 1972 Pulmonary MedicineshipPositions and Honors1974-1981 Assistant Professor of Medicine in Residence, University ofCalifornia, San Francisco.1981-1987 Associate Professor of Medicine in Residency, University ofCalifornia, San Francisco.1986- Present Member, Senior Staff, Cardiovascular Research Institute, Universityof California, San Francisco1987-1989 Professor of Medicine in Residence, University of California, SanFrancisco.1989-Present Professor of Medicine, University of California, San Francisco.1989-1995 Vice Chairman for Clinical Affairs, Department of Medicine,University of California, San Francisco1996-2009 Chief, Allergy/Immunology Division, Department of Medicine,University of California, San FranciscoMedical Licenses and Board CertificationCalifornia License Number A 023453American Board of Internal Medicine, June 1972Subspecialty Board of Pulmonary Medicine, October 1974102

Medical Society Memberships2003-May 2004Honors and AwardsPast-President - American Thoracic SocietyCalifornia Thoracic SocietyAmerican Federation for Clinical ResearchAmerican Physiological SocietyCalifornia Academy of MedicineWestern Society for Clinical InvestigationWestern Association of Physicians1964 Phi Beta Kappa1967 AOA1964-1968 Regents' Scholar1968 Gold-Headed Cane Recipient1977 H. J. Kaiser Award for Excellence in Teaching1988, ’90, ’95, Faculty-Student Teaching Award for "An Outstanding Lecture"99, 20001993 Clean Air Award (Education/Research), American Lung Association,San Francisco1993 California Medal, American Lung Association-California1996 UCSF Alumnus of the Year Award1997-2000 Bay Area’s Best Physicians, San Francisco Focus Magazine2000 Medical Student Teaching Award: “An Outstanding ClinicalCorrelation Lecturer”Selected peer-reviewed publications (in chronological order)1. Fahy JV, Wong H, Liu J, Boushey HA. Comparison of samples collected by sputuminduction and bronchoscopy from asthmatic and healthy subjects. Am J Respir Crit CareMed 1995;152:53-58.2. Fahy JV, Kim KW, Liu J, Boushey HA. Prominent neutrophilic inflammation in sputumfrom subjects with asthma exacerbation. J Allergy Clin Immunol 1995;95(4): 843-852.3. Drazen JM, Israel E, Boushey HA, Chinchilli VM, Fahy JV, Fish JE, Lazarus SC,Lemanske RF, Martin RJ, Peters SP, Sorkness C, Szefler SJ, for the National Heart,Lung, and Blood Institute’s Asthma Clinical Research Network. Comparison ofregularly scheduled with as-needed use of albuterol in mild asthma. N Engl J Med 1996;335:841- 47.4. Fahy JV, Fleming HE, Wong HH, Liu JT, Su JQ, Reimann J, Fick RB, Boushey HA.The effect of an anti-IgE monoclonal antibody on the early and late phase responses toallergen inhalation in asthmatic subjects. Am J Respir Crit Care Med 1997; 155:1828-34.5. Fleming HE, Little FF, Schnurr D, Avila PC, Wong H, Liu J, Yagi S, Boushey HA.Rhinovirus-16 colds in healthy and asthmatic subjects: similar changes in upper andlower airways. Am J Respir Crit Care Med 1999; 160:100-8.103

6. Lazarus S, Boushey H, Fahy J, Chinchilli V, Lemanske R, Sorkness C, Kraft M, Fish J,Peters S, Craig T, Drazen J, Ford J, Israel E, Martin R, Mauger E, Nachman S, Spahn J,Szefler S, and the Asthma Clinical Research Network. A randomized study of longactingbeta-agonist in patients with persistent asthma: I. monotherapy? JAMA 2001 May;23; 285: 2583-93.7. Wang D, Coscoy L, Zylberberg M, Avila PC, Boushey HA, Ganem D, DeRisi JL.Microarray-based detection and genotyping of viral pathogens. PNAS-2002; 99:15687-92.8. Lopez-Souza N, Dolganov G, Dubin R, Sporer H, Yagi S, Schurr D, Boushey H, et al.Resistance of Differentiated human airway epithelium to infection by rhinovirus. Am JPhysiol Lung Cell Mol Physiol. 2004 Feb; 286: L373-81.9. Boushey HA, Sorkness CA, King TS, Sullivan SD, Fahy JV, Lazarus SC, et al. “Dailyversus As-Needed Corticosteroids for Mild Persistent Asthma” New Eng J Med, 2005;352:1519-28.10. Stoloff SW, Boushey HA. Severity, Control, and Responsiveness in Asthma. J AllergyClin Immunol 2006: 117:544-8 (“Rostrum”)11. Kistler A, Avila PC, Rouskin S, Wang D, Ward T, Yagi S, Schnurr D, Ganem D, DeRisiJ, Boushey HA. “Pan-viral screening of respiratory tract infections in asthmatic and nonasthmaticadults reveals unexpected coronavirus and human rhinovirus diversity” J InfectDis. 2007 Sep 15:196(6):817-2512. Kistler A, Webster D, Rouskin S, Magrini V, Credle J, Schnurr D, Boushey HA, MardisE, Li H, DeRisi JL. “Genome-wide diversity and selective pressure in the humanrhinovirus.” Virol J. 2007 May 3; 4:40.13. Huang YJ, Nelson CE, Brodie EL, DeSantis TZ, Baek MS, Liu J, Woyke T, Allaier M,Bristow J, Wiener-Kronish JP, Sutherland ER, King TS, Icitovic N, Martin RJ, CalhounWJ, Castro M, Denlinger LC, DimangoE, Kraft M, Peters SP, Wasserman SI, WechslerME, Boushey HA, and Lynch SV. Airway microbiota andbronchial hyperresponsivenessin patients with sub-optimally controlled asthma. JACI 2011; 127:372-381.14. Wootton SC, Kim DS, Kondoh Y, Chen E, Lee JS, Song JW, Huh JW, Taniguchi H,Chiu C, Boushey HA, Lancaster LH, Wolters PJ, Derisi J, Ganem D, Collard HR. “ViralInfection in Acute Exacerbation of Idiopathic Pulmonary Fibrosis.” Am J Respir CritCare Med. 2011 Feb 2515. Calhoun WJ, Ameredes BT, King TS, Boushey HA. “Comparison of physician-based,biomarker-based, and symptom-based strategies for adjustment of inhaled corticosteroidtherapy in adults with asthma: The Basalt Randomized Trial.” JAMA. 2012 Sept 12;308:987-97.104

Research SupportOngoing Research SupportU10 HL098107(Boushey, HA) 09/30/09-06/30/16NIH/NHLBIUCSF AsthmaNet Clinical CenterThe major goals are to serve as a clinical center participating in the conduct of NHLBIsupportedmulti-center clinical trials of asthma therapies in children and adults with asthma, and toconductsmaller, focused studies of mechanisms of action of asthma therapies, of novel treatments forsevere asthma, and of concepts of asthma pathophysiology that could lead to the developmentof new asthma treatments. Role: Co-InvestigatorU10 HL0981(Boushey, HA) 09/30/09-06/30/16NIH/NHLBIUCSF AsthmaNet Clinical CenterThe major goals are to serve as a clinical center participating in the conduct of NHLBIsupportedmulti-center clinical trials of asthma therapies in children and adults with asthma, andto conduct smaller, focused studies of mechanisms of action of asthma therapies, of noveltreatments for severe asthma, and of concepts of asthma pathophysiology that could lead to thedevelopment of new asthma treatments. Role: Co-InvestigatorHHS N272200900052C(Boushey, HA) 09/30/09-09/29/14NIH/NIAIDInner-City Asthma Consortium II / UCSF ICAC-II Basic Science Site -The major goal is to serve as a Basic Science Site for the ICAC, enabling examination ofrelationships of the mirocrobial environment of inner city households, the development ofimmune function in infancy, and the development of allergic disease, especially asthma, inchildhood. Role: Principal InvestigatorP01 HL070831-06A1 (Lemanske, R) 05/01/08-04/30/13NIHRhinovirus Infection and Childhood AsthmaThe major goals of this study are to apply the Virochip microarray to search for novel viruses inrespiratory secretions obtained from children with severe clinical illnesses with the features of arespiratory infection but in whom standard PCR tests have not detected a virus, and further toexpand the ViroChip to detect regions of the rhinovirus genome associated with virulence.Role: Co-Investigator5 U10 HL074204-05NIH/NHLBI(Boushey, HA) 09/15/03-07/31/11105

Asthma Clinical Research Network Center at UCSFTo link the established clinical research group at the University of California, San Franciscowith other clinical research groups in an interactive network conducting collaborative studies ofnovel therapeutic approaches for asthma and disseminating the findings on optimalmanagement of asthmatic patients to practitioners and other health care professionals. Role:Principal Investigator5 U10 HL074431-05(Lazarus, SC) 08/15/03-07/31/11NIH/NHLBICOPD Clinical Research Network at UCSFHL-03-002 COPD Clinical Research NetworkThe purpose of the NIH-sponsored COPD Clinical Research Network is to evaluate new andexisting approaches for the management of COPD and to disseminate the findings of thisnetwork to the medical community. Role: Co-InvestigatorCompleted Research SupportR01 HL080414-05 (Fahy, JV) 07/01/05-05/31/10NIHHistoblood group antigens, viruses & asthmaThe major goals are to understand how expression of histo-blood groups antigens by airwayepithelial cells and airway mucins influences susceptibility to asthma exacerbations. Role: Co-InvestigatorR01 HL080074-01 (Cabana, M) 07/01/04-06/30/10NIHTrial of Infant Probiotic Exposure on Developing AsthmaThis trial will measure the effect of a 6-month daily exposure of Lactobacillus, as an infantformula supplement, on immune system and asthma development during the first 3 years of life.Role: Co-InvestigatorDoris Duke Foundation (Ganem, DE) 10/01/03-6/30/09Genomics-based Approaches to New Pathogen Discovery in Chronic Human DiseasesTo use a DNA microarray designed to detect any known virus to explore whether viruses areassociated with liver and lung diseases that are currently of unknown etiology. Role: PIAI050496-01(Boushey, HA) 09/01/01-04/31/06NIHAI-00-012 Asthma and Allergic Diseases Research Centers -- Rhinoviruses, Epithelial Cells,and Airway Function The purpose of this Program Project Grant is to examine the hypothesisthat the nature and intensity of the nasal and bronchial responses to Rhinovirus infection isdetermined by properties inherent to the infecting strain, and/or properties inherent to theepithelial cells infected. Role: PI106

NAMEEsteban González Burchard, M.D., M.P.H.eRA COMMONS USER NAMEEburchardBIOGRAPHICAL SKETCHPOSITION TITLEProfessor, Bioengineering & Therapeutic Sciences andMedicineDirector, Center on Genes, Environments & HealthEDUCATION/TRAININGINSTITUTION AND LOCATION DEGREE YEAR(s) FIELD OF STUDYSan Francisco State University, San Francisco, CA B.S. 1984-1990Cellular & MolecularBiologyStanford University School of Medicine,Stanford, CAM.D.1990-1995 MedicineProgram in ClinicalHarvard School of Public Health, Boston, MA Certificate 1997EffectivenessBrigham and Women's Hospital, Boston, MA Resident 1995-1998 Internal MedicineUniversity of California, San Francisco, SF, CA Fellow 1998-2001Pulmonary & Critical CareMedicineStanford University, Stanford, CA2001-2002 Genetic EpidemiologyUniversity of California, Berkeley M.P.H. 2005-2006 EpidemiologyPositions and Honors2001 - 2010 Director, UCSF DNA Bank and Asthma Genetics Core Facility2008 - Director, UCSF Center on Genes, Environments & Health2009 - Director, UCSF Clinical Pharmacology Training Program2010 - Vice Chair, Department of Bioengineering & Therapeutic Sciences, UCSF2011 - Professor, Bioengineering & Therapeutic Sciences and Medicine, UCSF1988, 1989 National Collegiate Athletic Association (NCAA)Div. II Academic All-American, Wrestling2005 – 2010 RWJ Amos Medical Faculty Development Award2008 NIH Study Section Member, Genetics of Health and Disease (GHD)2009 American Society of Clinical Investigation (ASCI), inducted member2009 Guest Speaker, Tavis Smiley Show2010 Guest Speaker, NPR’s Science Friday, hosted by Ira Flatow2011 Athletic Hall of Fame, San Francisco State University107

Selected Peer-reviewed Publications (selected from 86 publications)1. Burchard EG, Ziv E, Coyle N, Lin-Gomez S, Tang H, Karter AJ, Mountain J, Perez-Stable EJ, Sheppard D, Risch N. (2003) The Importance of Race and Ethnic Backgroundin Biomedical Research and Clinical Practice. N. Engl. J. Med. 348:1077-1192.2. Burchard EG, Avila PC, Nazario S, Casal J, Torres A, Rodriguez-Santana JR, ToscanoM, Senter-Sylvia J, Alioto ME, Salazar M, Gomez I, Fagan JK, Salas J, Lilly C,Matallana H, Ziv E, Castro R, Selman M, Chapela R, Sheppard D, Weiss ST, Ford JG,Boushey HA, Rodriguez-Cintron W, Drazen JM, Silverman EK (2004) LowerBronchodilator Responsiveness in Puerto Rican than in Mexican Asthmatic Subjects. Am.J. Respir. Crit. Care Med. 169:386-92.3. Salari K, Choudhry S, Tang H, Naqvi M, Lind D, Avila PC, Coyle NE, Ung N, NazarioS, Casal J, Torres-Palacios A, Clark S, Phong A, Gomez I, Matallana H, Perez-Stable EJ,Shriver MD, Kwok PY, Sheppard D, Rodriguez-Cintron W, Risch NJ, Ziv E, BurchardEG. (2005) Genetic admixture and asthma-related phenotypes in Mexican American andPuerto Rican asthmatics. Genet. Epidemiol. 29:76-86.4. Burchard EG, Borrell LN, Choudhry S, Naqvi M, Tsai HJ, Rodriguez-Santana JR,Chapela R, Rogers SD, Mei R, Rodriguez-Cintron W, Arena JF, Kittles R, Perez-StableEJ, Ziv E, Risch N. (2005) Latino Populations: A unique opportunity for the study ofrace, genetics and social environment in epidemiologic research. Am. J. Public Health95:2161-8.5. Tsai HJ, Kho JY, Shaikh N, Choudhry S, Naqvi M, Navarro D, Matallana H, Castro R,Lilly CM, Watson HG, Meade K, Le Noir M, Thyne S, Ziv E, Burchard EG. (2006)Admixture-matched case-control study: A practical approach for genetic associationstudies in admixed populations. Hum. Genet. 118:626-39.6. Tang H, Choudhry S, Mei R, Morgan M, Rodriguez-Cintron W, Burchard EG, Risch NJ(2007) Recent genetic selection in the ancestral admixture of Puerto Ricans. Am. J. Hum.Genet. 81:626-33 (PMC1950843).7. Choudhry S, Taub M, Mei R, Rodriguez-Santana J, Rodriguez-Cintron W, Shriver MD,Ziv E, Risch NJ, Burchard EG (2008) Genome-wide screen for asthma in PuertoRicans: Evidence for association with 5q23 region. Hum. Genet. 123:455-68(PMC2664533).8. Galanter J, Choudhry S, Eng C, Nazario S, Rodriguez-Santana J, Casal J, Torres A, SalasJ, Chapela R, Watson HG, Meade K, LeNoir M, Rodriguez-Cintron W, Avila PC,Burchard EG (2008) ORMDL3 gene is associated with asthma in three ethnicallydiverse populations. Am. J. Resp. Crit. Care Med. 177:1194-200 (PMC2408437).9. Seibold MA, Reese TA, Choudhry S, Salam MT, Beckman K, Eng C, Atakilit A, MeadeK, Lenoir M, Watson HG, Thyne S, Kumar R, Weiss KB, Grammer LC, Avila P,Schleimer RP, Fahy JV, Rodriguez-Santana J, Rodriguez-Cintron W, Boot RG, SheppardD, Gilliland FD, Locksley RM, Burchard EG (2009) Differential enzymatic activity ofcommon haplotypic versions of the human acidic mammalian chitinase protein. J. Biol.Chem. 284:19650-8 (PMC2740590).108

10. Hancock DB, Romieu I, Shi M, Sienra-Monge JJ, Wu H, Chiu GY, Li H, del Rio-Navarro BE, Willis-Owens SA, Weiss ST, Raby BA, Gao H, Eng C, Chapela R,Burchard EG, Tang H, Sullivan PF, London SJ (2009) Genome-wide association studyimplicates chromosome 9q21.31 as a susceptibility locus for asthma in Mexican children.PLoS Genet. 5:e1000623 (PMC2722731).11. Risch N, Choudhry S, Via M, Basu A, Sebro R, Eng C, Beckman K, Thyne S, Chapela R,Rodriguez-Santana J, Rodriguez-Cintron W, Avila PC, Ziv E, Burchard EG (2009)Ancestry-related assortative mating in Latino populations. Genome Biol. 10:R132.12. Mathias RA, Grant AV, Rafaels N, Hand T, Gao L, Vergara C, Tsai YJ, Yang M,Campbell M, Foster C, Gao P, Togias A, Hansel NN, Diette G, Adkinson NF, Liu MC,Faruque M, Dunston GM, Watson HR, Bracken MB, Hoh J, Maul P, Maul T, JedlickaAE, Murray T, Hetmanski JB, Ashworth R, Ongaco CM, Hetrick KN, Doheny KF, PughEW, Rotimi CN, Ford J, Eng C, Burchard EG, Sleiman PM, Hakonarson H, Forno E,Raby BA, Weiss ST, Scott AF, Kabesch M, Liang L, Abecasis G, Moffatt MF, CooksonWO, Ruczinski I, Beaty TH, Barnes KC (2010) A genome-wide association study onAfrican-ancestry populations for asthma. J. Allergy Clin. Immunol. 125:336-46. *13. Kumar R*, Seibold MA*, Aldrich MC*, Williams KL*, Reiner AP, Colangelo L,Galanter J, Gignoux C, Hu D, Sen S, Choudhry S, Peterson EL, Rodriguez-Santana J,Rodriguez-Cintron W, Nalls MA, Leak TS, O'Meara E, Meibohm B, Kritchevsky SB, LiR, Harris TB, Nickerson DA, Fornage M, Enright P, Ziv E, Smith LJ, Liu K, BurchardEG. (2010) Genetic ancestry and lung function predictions. New England Journal ofMedicine. 2010 Jul 22;363(4):321-30. Epub 2010 Jul 7.14. Tcheurekdjian, H.*, Via, M.*, De Giacomo, A., Corvol, H., Eng, C., Thyne, S., Chapela,R., Rodriguez-Cintron, W., Rodriguez-Santana, J., Avila, P.C., González Burchard, E.,on behalf of the Genetics of Asthma in Latino Americans (GALA) Study. *These authorscontributed equally to this manuscript. ALOX5AP and LTA4H polymorphisms modifyaugmentation of bronchodilator responsiveness by leukotriene modifiers in Latinos. JAllergy Clin Immunol. 2010 Oct; 126(4):853-8.*15. Kenny, E.E., Timpson, N.J., Sikora, M., Yee, M.C., Moreno Estrada, A., Eng, C.,Huntsman, S., Gonzalez Burchard, E., Stoneking, M., Bustamante, C.D., Myles, S.,Blond hair is caused by an amino acid change in TYRP1. Science. 2012 May4;336(6081):554Manuscripts in under review1. Luisa N. Borrell, Elizabeth A. Nguyen, Lindsey A. Roth,Sam S. Oh, HaigTcheurekdjian,Saunak Sen, Adam Davis, Harold J. Farber, Pedro C. Avila, EmeritaBrigino-Buenaventura, Michael A. LeNoir, Fred Lurmann, Kelley Meade, DeniseSerebrisky, William Rodriguez-Cintron, Rajesh Kumar, Jose R. Rodriguez-Santana,Shannon Thyne, Esteban G. Burchard. Childhood obesity and asthma control in adiverse sample: Examining age and racial/ethnic differences. AJRCCM. (Under 2ndreview January 2013).109

2. Rajesh Kumar, Elizabeth A Nguyen, Lindsey A Roth, Sam S Oh,Christopher R Gignoux,Scott Huntsman, Celeste Eng, Andres Moreno-Estrada, Karla Sandoval, RosendaPeñaloza-Espinosa, Marisol López-López, Pedro C Avila, Harold J Farber, HaigTcheurekdjian, William Rodriguez-Cintron, Jose R Rodriguez-Santana, DeniseSerebrisky, Shannon M Thyne, Keoki Williams, William Klitz, Cheryl Winkler, Carlos DBustamante, Eliseo J Pérez-Stable, Luisa N Borrell, Esteban G Burchard. Factorsassociated with degree of atopy in Latino children in a nationwide pediatric sample: TheGALA II Study. J Allergy Clin Immunol. (Under 2 nd review, December 2013).3. Joshua M Galanter, Christopher R Gignoux, Dara G Torgerson, Lindsey A Roth, CelesteEng, Sam S Oh, Elizabeth A Nguyen Scott Huntsman Donglei Hu, Saunak Sen. AdamDavis, Harold J. Farber, Pedro C. Avila, Emerita Brigino-Buenaventura, Michael A.LeNoir, Kelley Meade, Denise Serebrisky, Stephanie London, Frank Gilliland, FernandoMartinez, Luisa N Borrell, William Rodriguez-Cintron, Rajesh Kumar, Jose R.Rodriguez-Santana, Esteban G. Burchard, and the EVE Consortium. Genome-wideassociation and admixture mapping identify chromosomal regions 17q21 and 6p21 asasthma-associated loci in Latinos. AJRCCM. (Under review December 2013).4. Chris R Gignoux, Dara G Torgerson, Joshua Galanter, Lindsey A Roth, Celeste Eng,Elizabeth A Nguyen, Scott Huntsman, Sam S Oh,Raskia A Mathias, Adam Davis, HaroldJ Farber, Pedro C Avila, Emerita Brigino-Buenaventura, Michael A LeNoir, KelleyMeade, Denise Serebrisky, Luisa N Borrell, William Rodriguez-Cintron, Rajesh Kumar,Jose R Rodriguez-Santana, Andres Moreno, Karla Sandoval, Cheryl Winkler, CarlosBustamante, EVE Collaborators, Carole Ober, Dan Nicholae, Saunak Sen, Kathleen CBarnes, Esteban G Burchard. Meta-analysis of admixture mapping using existinggenome-wide association data implicates SMAD2 as a novel asthma-associated locus inLatinos. Nature Genetics. (Submitted Jan 2013).5. Katherine A. Drake, Dara G. Torgerson, Christopher R. Gignoux, Joshua M. Galanter,Lindsey A. Roth, Scott Huntsman, Celeste Eng, Sam S. Oh, Sook Wah Yee, LawrenceLin, Adam Davis, Luisa N. Borrell, Harold J. Farber, Rajesh Kumar, Pedro C. Avila,Emerita Brigino-Buenaventura, Rocio Chapela, Jean G. Ford, Michael A. LeNoir, FredLurmann, MS, Kelley Meade, Denise Serebrisky, Shannon Thyne, William Rodríguez-Cintrón, Saunak Sen, José R. Rodríguez-Santana, Kathleen M. Giacomini, and EstebanG. Burchard. A Genome-wide Association Study of Bronchodilator Response inLatinos Implicates Rare Variants. J Allergy Clin Immunol. (Submitted January 2013).6. Katherine K. Nishimura, Joshua M. Galanter, Lindsey A. Roth, Sam S. Oh, Harold J.Farber, Denise Serebrisky, Rajesh Kumar, Luisa N. Borrell, Emerita Brigino-Buenaventura, Adam Davis, Michael A. LeNoir, Kelley Meade, William Rodriguez-Cintron, Pedro C. Avila, Jose R. Rodriguez-Santana, Saunak Sen, Fred Lurmann, John R.Balmes, Esteban G. Burchard. Early Life Exposure to Air Pollution and the Risk ofAsthma in Latino and African American Children. ARJCCM. (Submitted January 2013).110

Research SupportOngoing Research Support1R01 HL104608-01A1 (PI: Barnes) 09/28/2011-6/30/2015Source: Johns Hopkins University-SubcontractRole: SubcontractorProject title: New Approaches for Empowering Studies of Asthma in Populations of African DescentThe major goal of this project is to identify genetic variants specific to African populations. We willsequence Latino and African American samples to design a custom GeneChip for populations withAfrican ancestry.P60 MD006902 (PI: Bibbins-Domingo) 03/01/13-02/28/17Source: NIH/NIMHDRole: Project PIProgram title: Addressing Disparities in Chronic Disease with a Teen and Young AdultFocusProject title: The Genetics of Asthma and Obesity Using Admixture Mapping in LatinosThe major goal of this proposal is to identify novel genetic variants associated with bothasthma and obesity by deep re-sequencing of candidate regions identified throughadmixture mapping.R01 ES015794 (PI: Burchard) 9/01/08-5/31/13Source: NIH/NIEHSProject title: Genes-environments & Admixture in Latino Asthmatics (GALA 2)The major goal of this project is to identify genetic, social and environmental riskfactors for asthma among various Latino groups recruited throughout the U.S.R01 HL088133 (PI: Burchard) 3/01/08-2/28/13Source: NIH/NHLBIProject title: Whole Genome Analyses for Asthma in Latino PopulationsThe major goal of this project is to perform genome-wide association analyses toidentify genetic factors associated with asthma and related phenotypes in PuertoRicans and Mexicans.U19 AI077439 (PI: Sheppard) 04/01/08-03/31/13Source: NIH/NIAIDRole: Project 3 PIProgram title: Mechanisms of Initiation and Persistence of Allergic AsthmaProject 3 title: Chitinases and TGFb in Human AsthmaThe goal is to analyze the effects of genetic variation on genes in the TGF beta andChitinase pathways and their role in the initiation and persistence of asthma acrossracial and ethnically diverse populations.111

Completed Research(Neal Benowitz, Program PI) 07/01/07-06/30/12Role on project: Project 7 PISource: Flight Attendants Medical Research Institute (FAMRI)Program title: UCSF Center of Excellence on Secondhand SmokeProject title: Tobacco Gene–Environment Interactions in African American and LatinoAsthmatics. The goal is to identify gene-environment interactions between asthma andsecondhand smoke.RC2 HL101651 (Co-PIs: Ober, Nicolae) 09/30/09-09/29/11NIH/R01Role on project: SubcontractorThe EVE Asthma Genetics Consortium: Building Upon GWASTo replicate the most significant GWAS (meta-analysis) results in >15,000 asthma casesand controls of European American, African American, and U.S. Hispanic ethnicities, resequence5-10 genes associated with asthma in European Americans but not in AfricanAmericans or Hispanics, to study additional asthma-associated phenotypes and examineinteractions, and develop methods to facilitate gene discovery.U01 GM61390 (PI:Giacomini) 07/20/05-06/30/10Role on project: Co-InvestigatorSource: NIH/NIGMSProgram title: Pharmacogenetics of Membrane TransportersProject title: Study of Pharmacogenetics in Ethically Diverse GroupsThe goal was to develop an ethnically diverse cohort of subjects to participate inpharmacogenetic studies.R01 HL078885 (PI: Burchard) 08/15/05-07/31/10Source: NIH/NHLBIProject title: Case-control Association Studies and Genetic ConfoundingThe goal was to test and compare methods of detecting and correcting for populationstratification.112

BIOGRAPHICAL SKETCHNAMEGeorge H. CaugheyeRA COMMONS USER NAMEgcaugheyPOSITION TITLEProfessor of MedicineINSTITUTION AND LOCATIONEDUCATION/TRAININGDEGREEYEAR(s)FIELD OF STUDYArizona State University BS 1975 ChemistryStanford University School of Medicine MD 1979 MedicinePennsylvania Hospital/UPenn 1982 Internal MedicineUniversity of California, San Francisco 1986 Pulmonary MedicinePositions and Honors1988-92 Assistant Professor, Dept. of Medicine, UCSF1988-98 Associate Staff, Cardiovascular Research Institute, UCSF1992-98 Associate Professor, Dept. of Medicine, UCSF1992- Molecular Medicine Program Faculty, UCSF1995- Editorial Board, American Journal of Respiratory Cell and Molecular Biology1996- Member of UCSF Graduate Program in Biomedical Sciences1998- Professor, Dept. of Medicine, UCSF1999- Investigator, Cardiovascular Research Institute, UCSF2002- Member, UCSF Cancer Center and Center for Neurobiology of Digestive Disease2004- Editorial Board, Current Respiratory Medicine Reviews2004- Chief of Pulmonary and Critical Care and Sleep Medicine,San Francisco VA Medical Center2012- Associate Chief of Research and Academic Affairs, Medical ServiceSan Francisco VA Medical CenterHonors and Awards1974 American Chemical Society Outstanding Undergraduate Award, ASU1975 Phi Beta Kappa and Merck Award in Chemistry, ASU1986 NIH Clinical Investigator Award1992 American Lung Association Career Investigator Award1992 Elected to American Society for Clinical Investigation113

2000 Elected to American Association of Physicians2004- Julius and Lillian Nadel Endowed Chair of Medicine2010 Elected to Collegium Internationale AllergologicumPublications in chronological order (selected from 135)1. Vanderslice P, Ballinger SM, Tam EK, Goldstein SM, Craik CS, Caughey GH. Humanmast cell tryptase: multiple cDNAs and genes reveal a multigene protease family. ProcNatl Acad Sci USA 87:3811-5, 1990.2. Rubinstein I, Nadel JA, Graf PD, Caughey GH. Mast cell chymase potentiateshistamine-induced wheal formation in the skin of ragweed-allergic dogs. J Clin Invest86:555-9, 1990.3. Ruoss SJ, Hartmann T, Caughey GH. Mast cell tryptase is a mitogen for culturedfibroblasts. J Clin Invest 88:493-9, 1991.4. Caughey GH, Raymond WW, Bacci E, Lombardy RJ, Tidwell RR. BABIM and relatedamidines are potent, reversible inhibitors of mast cell tryptases. J Pharmacol Exp Therap264:676-82, 1993.5. Caughey GH, Schaumberg TH, Zerweck EH, Butterfield JH, Hanson RD, SilvermanGA, Ley TJ. The human mast cell chymase gene (CMA1): mapping to the cathepsinG/granzyme gene cluster and lineage-restricted expression. Genomics 15:614-20, 1993.6. Fang KC, Raymond WW, Lazarus SC, Caughey GH. Dog mastocytoma cells secrete a92 kDa gelatinase activated extracellularly by mast cell chymase. J Clin Invest 97:1589-96, 1996.7. Fang KC, Raymond WW, Blount JL, Caughey GH. Dog mast cell a-chymase activatesprogelatinase B by cleaving Phe 88 -Gln 89 and Phe 91 -Glu 92 bonds of the propeptide domain.J Biol Chem 272:25628-35, 1997.8. Wolters PJ, Raymond WW, Blount JL, Caughey GH. Regulated expression, processingand secretion of dog mast cell dipeptidyl peptidase I. J Biol Chem 273:15514-20, 1998.9. Pallaoro M, Fejzo MS, Shayesteh L, Blount JL, Caughey GH. Characterization of genesencoding known and novel human tryptases on chromosome 16p13.3. J Biol Chem274:3355-62, 1999.10. Ma Y, Longley BJ, Blount JL, Langley K, Caughey GH. Clustering of activatingmutations in c-kit’s juxta-membrane coding region in canine mastocytomas. J InvestDermatol 112:165-70, 1999.11. Coussens LM, Raymond WW, Bergers G, Behrendtsen O, Werb Z, Caughey GH,Hanahan D Inflammatory mast cells potentiate the angiogenic switch during squamousepithelial carcinogenesis. Genes & Development 13:1382-97, 1999.12. Caughey GH, Raymond WW, Blount JL. Hau LW-T, Pallaoro M, Wolters PJ, VergheseGM. Characterization of human g-tryptases, novel members of the chromosome 16p mastcell tryptase and prostasin gene families. J Immunol 164:6566-75, 2000.13. Steinhoff M, Vergnolle N, Young S, Ennes H, Hollenberg MD, Wallace JL, CaugheyGH, Williams LM, Geppetti P, Mayer EA, Bunnett NW. Agonists of proteinaseactivatedreceptor 2 induce inflammation by a neurogenic mechanism. Nature Med6:151-8, 2000.114

14. Frank BT, Rossall JC, Caughey GH, Fang KC. Mast cell tissue inhibitor ofmetalloproteinase-1 is cleaved and inactivated extracellularly by a-chymase. J Immunol166:2783-92, 2001.15. Wolters PJ, Muilenburg D, Pham CTN, Ley TJ, Caughey GH. Dipeptidylpeptidase I isessential for in vivo activation of mast cell chymases, but not tryptases. J Biol Chem276:18551-6, 2001.16. Muilenburg DJ, Raymond WW, Wolters PJ, Caughey GH. Lys 40 but not Arg 143influences selectivity of angiotensin conversion by human a-chymase. Biochim BiophysActa 1596:346-56, 2002.17. Soto D, Malmsten C, Blount JL, Muilenberg DJ and Caughey GH. Genetic deficiency ofhuman mast cell a-tryptase. Clin Exp Allergy 32:1000-6, 2002.18. Bhagwandin VJ, Hau L W-T, Mallen-St. Clair J, Wolters PJ, Caughey GH. Structureand activity of pancreasin, a novel tryptic serine peptidase expressed by pancreas. J BiolChem 278:3363-71, 2003.19. Reiling KK, Krucinski J, Miercke LJW, Raymond WW, Caughey GH, Stroud RM.Structure of human pro-chymase. Biochemistry 42:2616-24, 2003.20. Raymond WW, Ruggles Waugh S, Craik CS, Caughey GH. Albumin is a substrate ofhuman chymase: prediction by combinatorial peptide screening and development of aselective inhibitor based on the cleavage site. J Biol Chem 278:34517-24, 2003.21. Mallen-St. Clair J, Pham CTN, Villalta SA, Caughey GH, Wolters PJ. Mast celldipeptidyl peptidase I mediates survival from sepsis. J Clin Invest 113:628-34, 2004.22. Verghese GM, Tong ZY, Bhagwandin V, Caughey GH. Mouse prostasin gene structure,promoter function, and restricted expression in lung and kidney. Am J Respir Cell MolBiol 30:519-29, 2004.23. Baluk P, Raymond WW, Ator E, Coussens LM, McDonald DM, Caughey GH. MMP-2and -9 expression increases in mycoplasma-infected airways but is not required formicrovascular remodeling. Am J Physiol 287:L307-17, 2004.24. Raymond WW, Sommerhoff CP, Caughey GH. Mastin is a gelatinolytic mast cellpeptidase resembling a mini-proteasome. Arch Biochem Biophys 435:311-22, 2005.25. Tong ZY, Illek B, Bhagwandin VK, Verghese GM, Caughey GH. Prostasin, amembrane-anchored serine peptidase, regulates sodium currents in JME/CF15 cells, acystic fibrosis epithelial cell line. Am J Physiol 287:L928-35, 2004.26. Wolters PJ, Mallen-St. Clair J, Lewis CC, Villalta SA, Baluk P, Erle DJ, Caughey GH.Tissue-selective mast cell reconstitution and differential lung gene expression in mastcell-deficient Kit W-sh /Kit W-sh sash mice. Clin Exp Allergy 35:82-8, 2005.27. Xu X, Golden JA, Dolganov G, Jones KD, Donnelly S, Weaver T, Caughey GH.Transcript signatures of lymphocytic bronchitis in lung allograft biopsies. J Heart LungTransplant 24:1055-66, 2005.28. Xu X, Zhang D, Lyubynska N, Wolters PJ, Killeen NP, Baluk P, McDonald DM,Hawgood S, Caughey GH. Mast cells protect mice from mycoplasma pneumonia. Am JResp Crit Care Med 173:219-25, 2006.29. Raymond WW, Cruz AC, Caughey GH. Mast cell and neutrophil peptidases attack aninactivation segment in hepatocyte growth factory to generate NK4-like antagonists. JBiol Chem 281:1489-94, 2006.115

30. Caughey GH. Tryptase genetics and anaphylaxis. J Allergy Clin Immunol 117:1411-4,2006.31. Mallen-St Clair J, Shi G-P, Sutherland RE, Chapman HA, Caughey GH, Wolters PJ.Cathepsins L and S are not required for activation of dipeptidyl peptidase I in mice. BiolChem 387:1143-6, 2006.32. Verghese GM, Gutknecht MF, Caughey GH. Prostasin regulates epithelial monolayerfunction: cell-specific Gpld1-mediated secretion and role of GPI anchor. Am J PhysiolCell Physiol 291:C1258-70, 2006.33. Caughey GH. A pulmonary perspective on GASPIDs: Granule-Associated SerinePeptidases of Immune Defense. Curr Resp Med Rev 2:263-77, 2006.34. Xu X, Zhang D, Zhang H, Wolters PJ, Killeen NP, Sullivan BM, Locksley RM, LowellCA, Caughey GH. Neutrophil histamine contributes to inflammation in mycoplasmapneumonia. J Exp Med 203:2907-17, 2006.35. Planès C and Caughey GH. Regulation of the epithelial Na+ channel by peptidases. CurrTop Dev Biol 78:23-46, 2007.36. Caughey GH. Mast cell tryptases and chymases in inflammation and host defense.Immunol Rev 217:114-54, 2007.37. Akin C, Soto D, Brittain E, Chhabra A, Schwartz LB, Caughey GH, Metcalfe DD.Tryptase haplotype in mastocytosis: Relationship to disease variant and diagnostic utilityof total tryptase levels. Clin Immunol 123:268-71, 2007.38. Trivedi NN, Tong Q, Raymond WW, Bhagwandin VJ, Caughey GH. Mast cell tryptaseschanged rapidly during primate speciation and evolved from g-like transmembranepeptidases in ancestral vertebrates. J Immunol 179:6072-9, 2007.39. Caughey GH. “Mast Cells and Basophils” in Asthma and COPD—Basic Mechanismsand Clinical Management, Barnes PJ, Drazen JM, Rennard S, Thompson NC, eds.,Academic Press, London, 2008.40. Trivedi NN, Raymond WW, Caughey GH. Chimerism, point mutation and truncationdramatically transformed mast cell d tryptases during primate evolution. J Allergy ClinImmunol 121:1262-8, 2008.41. Caughey GH, Beauchamp J, Schlatter D, Raymond WW, Trivedi NN, Banner D, MauserH, Fingerle J. Guinea pig chymase is leucine-specific: a novel example of functionalplasticity in the chymase/granzyme family of serine peptidases. J Biol Chem 283:13943-51, 2008.42. Raymond WW, Su S, Makarova A, Wilson TM, Carter MC, Metcalfe DD, Caughey GH.a 2 -Macroglobulin capture allows detection of mast cell chymase in serum and creates areservoir of angiotensin II-generating activity. J Immunol 182:5770-7, 2009.43. Innes AL, Carrington SD, Thornton DJ, Kirkham S, Dougherty RH, Raymond WW,Caughey GH, Muller SJ, Fahy JV. Ex vivo sputum analysis reveals impairment ofprotease-dependent mucus degradation by plasma proteins in acute asthma. Am J RespCrit Care Med 180:203-10, 2009.44. Trivedi NN, Tamraz B, Chu C, Kwok PY, Caughey GH. Humans are protected frommast cell tryptase deficiency despite frequent inheritance of loss-of-function mutations. JAllergy Clin Immunol 124:1099-105, 2009.116

45. Trivedi NN and Caughey GH. Mast cell peptidases: chameleons of innate immunity andhost defense. Am J Respir Cell Mol Biol 42:257-67, 2010.46. Dougherty RH, Sidhu SS, Raman K, Solon M, Solberg OD, Caughey GH, WoodruffPG, Fahy JV. Accumulation of intraepithelial mast cells with a unique proteasephenotype in Th2-high asthma. J Allergy Clin Immunol, 125:1046-53, 2010.47. Raymond WW, Trivedi NN, Makarova A, Ray M, Craik CS, Caughey GH. Howimmune peptidases change specificity: Cathepsin G gained tryptic function but lostefficiency during primate evolution. J Immunol 185:5360-8, 2010.48. Caughey GH. “Mast cell proteases as protective and inflammatory mediators”, in MastCell Biology: Contemporary and Emerging Topics, Gilfillan AM and Metcalfe DD, eds.,Landes Bioscience, 2011.49. Caughey GH. “Protease mediators of anaphylaxis”, in Anaphylaxis and HypersensitivityReactions: From Molecular Markers to Rapid Desensitizations, Castells A, ed., SpringerInc., 2011.50. Xu X, Zhang H, Song Y, Lynch SV, Lowell CA, Wiener-Kronish JP, Caughey GH.Strain-dependent induction of neutrophil histamine production and cell death byPseudomonas aeruginosa. J Leuk Biol, in press, epub 2011.51. Sutherland SE. Xu X. Kim SS, Seeley EJ, Caughey GH, Wolters PJ. Parasitic infectionimproves survival from septic peritonitis by enhancing mast cell responses to bacteria inmice. PLoS One, 6(11):e27564, 2011.52. Sugimoto K, Kudo M, Sundaram A, Ren X, Huang K, Bernstein X, Wang Y, RaymondWW, Erle DJ, Åbrink M, Caughey GH, Huang X, Sheppard D. The α v β 6 integrinmodulates airway hyperresponsiveness in mice by regulating intra-epithelial mast cells. JClin Invest, in press.53. Nimishakavi S, Besprozvannaya M, Raymond WW, Craik CS, Gruenert DC, CaugheyGH. Activity and inhibition of prostasin and matriptase on apical and basolateral surfacesof human airway epithelial cells. Am J Physiol: Lung Cell Mol Physiol 303:L97-106,2012.54. Greenland JR, Jones KD, Hays SR, Golden JA, Urisman A, Jewell NP, Caughey GH,Trivedi NN. Association of large-airway bronchitis with bronchiolitis obliteranssyndrome. Am J Respir Crit Care Med, in press117

Research SupportOngoing Research Support"Evolving Microenvironments in Airway Inflammation"Project 1: Roles of Peptidases in Chronic Airway Inflammation; and Administrative Core AProgram Director/Project 1 Leader/Core Leader: George H. CaugheyAgency: NIH-NHLBI; Type: Program Project P01 HL024136; 05/11/2010-3/30/2015Project 1 goals are to determine roles of secreted proteases in airway inflammation.“Roles of Mast Cells in Primary Dysfunction of Lung Allografts”Principal Investigator: George H. CaugheyAgency: UCSF Nina Ireland Lung Research Program; 01/1/2012-12/31/2013The goals of this project are to explore roles of mast cells in primary graft dysfunction."Alloimmune Monitoring of Lung Transplant Recipients"Principal Investigator: Qizhi Tang; Co-I: George H. CaugheyAgency: UCSF Nina Ireland Lung Research Program; 01/1/2013-12/31/2015The goals of this project are to identify means of predicting and preventing graft dysfunction in lungallograft recipients.118

BIOGRAPHICAL SKETCHNAMEHarold A. Chapman, M.D.eRA COMMONS USER NAMEHalchapmanPOSITION TITLEProfessor of MedicineEDUCATION/TRAININGINSTITUTION AND LOCATION DEGREE YEAR(s) FIELD OF STUDYTulane University 1968 PremedicalUniversity of Alabama School of Medicine M.D. 1972 MedicinePositions and HonorsPositions1972-1975 Residency Training in Internal Medicine, University of Utah Affiliated Hospitals,Salt Lake City, UT1975-1977 Associate Investigator, V.A. Medical Center, Salt Lake City, UT1978-1979 Pulmonary Fellow, University of Utah Affiliated Hospitals, Salt Lake City, UT1979-1985 Assistant Professor of Medicine, University of Utah, Department of Medicine,Salt Lake City, UT1985 Associate Professor of Medicine, University of Utah, Department of Medicine,Salt Lake City UT1985-1999 Associate Professor of Medicine, Harvard Medical School, Department ofMedicine, Boston, MA1992-1999 Physician, Brigham and Women's Hospital, Boston, MA1992-1999 Associate Professor of Environmental Health, Harvard School of Public Health,Boston, MA2000-2008 Chief, Division of Pulmonary and Critical Care Medicine, University ofCalifornia, San Francisco2000 Professor of Medicine, University of California, San Francisco2000 Senior Member, Cardiovascular Research Institute, University of California SanFranciscoHonors1985-1990 Career Investigator Award, American Lung Association1987 American Society for Clinical Investigation1998 American Association of Physicians119

2001-2011 MERIT Award, NIH/NHLBIAd Hoc member of various NIH study sectionsEditorial Board of Journal of Clinical Investigation and Associate Editor,American Journal of Respiratory, Cell, and Molecular Biology.Selected Peer-reviewed Publications (Selected from ~140)1. Shi GP, Munger JS, Meara JP, Rich DH, Chapman HA. Molecular cloning andexpression of human alveolar macrophage cathepsin S, an elastinolytic cysteineprotease. J Biol Chem 1992 15; 267:7258-62.2. Wei Y, Waltz D, Rao N, Drummond R, Rosenberg S, Chapman HA. Identificationof the urokinase receptor as an adhesion receptor for vitronectin. J Biol Chem, 1994;209:32380-32388.3. Riese R, Wolf P, Bromme D, Natkin L, Villadangos JA, Ploegh H, and HAChapman. Essential role for cathepsin S in MHC Class II-associated invariant chainprocessing and antigen presentation. Immunity 1996;4:357-366.4. Gelb BD, Shi GP, Chapman HA Jr, Desnick RJ. Pycnodysostosis, a lysosomaldisease caused by cathepsin K deficiency. Science 1996; 273:1236-1238.5. Wei Y, Lukasev M, Simon DI, Bodary SC, Rosenberg S, Doyle MV, Chapman HA.Regulation of integrin function by the urokinase receptor. Science 1996; 273:1551-1555.6. Shi GP, Villadangos J, Dranoff G, Ploegh H, Chapman HA. Cathepsin S required fornormal MHC class II peptide loading and germinal center development. Immunity,1999;10:196-206.7. Tang CH, Lee JW, Galvez MG, Robillard L, Mole SE, Chapman HA. Murinecathepsin F deficiency causes neuronal lipofuscinosis and late-onset neurologicaldisease. Mol Cell Biol. 2006; 26 :2309-16.8. Kim KK, Kugler MC, Wolters PJ, Robillard L, Galvez MG, Brumwell AN, SheppardD, Chapman HA. Alveolar epithelial cell mesenchymal transition develops in vivoduring pulmonary fibrosis and is regulated by the extracellular matrix. Proc NatlAcad Sci 2006; 103(35):13180-5. Epub 2006 Aug 219. Ewald SE, Lee BL, Lau L, Wickliffe KE, Shi GP, Chapman HA, Barton GM. Theectodomain of Toll-like receptor 9 is cleaved to generate a functional receptor.Nature. 2008 Dec 4;456(7222):658-62.10. Kim KK, Wei Y, Szekeres C, Kugler MC, Wolters PJ, Hill ML, Frank JA, BrumwellAN, Wheeler SE, Kreidberg JA, Chapman HA. Epithelial cell alpha3beta1 integrinlinks beta-catenin and Smad signaling to promote myofibroblast formation andpulmonary fibrosis. J Clin Invest. 2009 Jan;119(1):213-24. See Commentary sameissue.11. Kim Y, Kugler MC, Wei Y, Kim KK, Li X, Brumwell AN, Chapman HA. Integrinalpha3beta1-dependent beta-catenin phosphorylation links epithelial Smad signalingto cell contacts. J Cell Biol. 2009 Jan 26;184(2):309-22.12. Chapman HA, Li X, Alexander JP, Brumwell A, Lorizio W, Tan K, Sonnenberg A,Wei Y, Vu T. Integrin α6β4 identifies an adult distal lung epithelial population with120

egenerative potential in mice. J Clin Invest. 2011, 121:2855-62. See Commentarysame issue.13. Ulsamer A, Wei Y, Kim KK, Tan K, Wheeler S, Xi Y, Thies RS, Chapman HA.Axin pathway activity regulates in vivo pY654-b-catenin accumulation andpulmonary fibrosis. J Biol Chem 2012, 287: 5164-5172.14. Sennino B, Ishiguro-Oonuma T, Wei Y, Naylor RM, Williamson CW, BhagwandinV, Tabruyn SP, You WK, Chapman HA, Christensen JG, Aftab DR, McDonaldDM. Suppression of tumor invasion and metastasis by concurrent inhibition of c-Metand VEGF signaling in pancreatic neuroendocrine tumors. Cancer Discovery 2012,2:270-287.15. Xi Y, Wei Y, Sennino, Ulsamer A, Kwan I, Brumwell AN, Tan K, Aghi MK,McDonald DM, Jablons DM, Chapman HA. Identification of pY654-b-catenin as acritical co-factor in hypoxia-inducible factor-1a signaling and tumor responses tohypoxia. Oncogene 2012, Dec 17. doi: 10.1038/onc.2012.530.16. Smith KR, Dahl HH, Canafoglia L, Andermann E, Damiano J, Morbin M,Franceschetti S, Cossette P, Saftig P, Grötzinger J, Schwake M, Andermann F,Staropoli JF, Sims KB, Mole SE, Alexander NA, Cooper JD, Chapman HA,Carpenter S, Berkovic SF, Bahlo M. Cathepsin F mutations cause type B Kufsdisease, an adult-onset neuronal ceroid lipofuscinosis. Human Molecular Genetics2013, Jan 12. [Epub ahead of print].Research SupportOngoing Research Support5 R37 HL67204 (Chapman, HA) No cost extension 6/1/2001 – 5/31/2013NIH/NHLBI MERIT AWARDRole of Elastolytic Cathepsins in EmphysemaThe major goal of this project is define the role of cysteine proteases in smoking-relatedemphysema. The project focuses on pathways of elastase expression in lung mesenchymalcells and on the genetics of emphysema in human subjects with early-onset emphysema andnormal alpha-1-antitrypsin.5 R01 HL44712 (Chapman, HA) $250,000 per yr directRegulation of Integrin Function 1/1/1991 – 12/31/2014The major goals of this project are to understand the molecular basis and importance ofintegrin function in promoting TGFb1 signaling and pulmonary fibrosis. The hypothesisthat epithelial to mesenchymal transition is an important component of pulmonary fibrosis,and regulated by integrins, is the main idea tested in this grant.5 R01 CA125564 (Chapman, HA) No cost extension 7/1/2007 – 5/31/2013121

NIH/NHLBIUrokinase Receptor Integrin Interactions in Lung CancerThe major goals of this project are to define the physical basis of urokiinase receptor beta1interactions and the influence of these interactions on tumor cell signaling and lung tumorprogression. Primary tumor cells from human tumors will be examined for their expressionand dependence on urokinase receptors for adhesion and migration.U01 HL111054-01 (Chapman HA, PI) $250,000 per year directNIH/NHLBIEpithelial Progenitor Cells in Lung Repair and Regeneration 1/1/2012-12/31/2016The major goals of this project are (1) To define the transcriptional program of heretoforeuncharacterized distal airway and alveolar progenitors and test the hypothesis that differentialexpression of adhesion receptors underlies the capacity of epithelial subtypes to self-organizeand promote repair. (2) Define the requirement for neuroendocrine cells (PNECS )andalveolar progenitor cells in maintenance and reconstitution of distal airway and alveolar cellsfollowing lung injury. (3) Analyze and further develop a novel, single cell in vivo lungorganoid assay in kidney capsules in order to optimize the capacity of adult epithelialprogenitor cells to generate functional respiratory units de novo.PO1 HL108794 (Sheppard PI, Chapman HA, project leader) 250,000 per year directTargeting epithelial cells to treat pulmonary fibrosis. 8/1/2012-7/31/2017The major goal of this project is to deliver one or more novel therapeutics based on recentlyidentified regulators of EMT in lung epithelial cells for further drug development.122

BIOGRAPHICAL SKETCHNAMEAnthony L. DeFranco, Ph.D.eRA COMMONS USER NAMEDeFrancoPOSITION TITLEProfessor,Department of Microbiology & ImmunologyEDUCATION/TRAININGINSTITUTION AND LOCATION DEGREE YEAR(s) FIELD OF STUDYHarvard University, Cambridge, MA A.B. 6/75 Biochem. & Molec.University of California, Berkeley, CA Ph.D. 10/79 Biol. BiochemistryNational Institutes of Health, Bethesda, MD Postdoctoral 11/79-8/83 ImmunologyPositions and Honors1972-1975 Undergraduate research, laboratory of Dr. Jack Strominger. HLA antigens.1976-1979 Graduate research, laboratory of Dr. Daniel E. Koshland, Jr. Bacterialchemotaxis.1979-1983 Postdoctoral research, laboratory of Dr. William E. Paul. B cell activation.1983-1988 Assistant Professor, UCSF, Department of Microbiology & Immunology,1988-1994 Associate Professor, UCSF, Department of Microbiology & Immunology1989-1990 Sabbatical with David Baltimore, Whitehead Insititute, MIT, Cambridge, MA1994-present Professor, UCSF, Department of Microbiology & Immunology1997-1998 Sabbatical with Suzanne Cory, Walter and Eliza Hall Institute, Melbourne,Australia1998-2004 Scientific Advisory Board, Abgenix, Inc. Fremont, CA1999-2009 Chairman, Department of Microbiology & Immunology, UCSF2012- Scientific Advisory Board, UCB Celtech, Slough, UK1974 Dreyfuss Foundation Fellow1975 Phi Beta Kappa, Harvard University1975-1978 NSF Predoctoral Fellow1979-1982 Helen Hay Whitney Postdoctoral Fellow; 2nd Rose Lieberman Lecturer, NIH1993 1994 NIAID Merit Award1997-1998 NIH Fogarty Senior International Award.123

Professional Service (selected list)Member Exptl. Immunol. Study Section (1993-97), Chair (1995-1997); NIH grant reviewer, adhoc (average 3 committees/yr since 2005, including TTT 2008, 2009); J. Immunol. AssociateEditor (1986-90), Section Editor (1990-1994), Deputy Editor (1999-2001); Annual Review ofImmunology, Editorial Committee for Volumes 9,13, 15, 17 (1991, ‘95, ‘97, ‘99); CurrentBiology, Editorial Board (1993-99). Lecturer, American Assoc. of Immunologists, AdvancedCourse 1995-97; Leukemia Society of America, Career Development Program Grant ReviewSubcommittee (1999-2005); Co-organizer: “B cell Immunobiology and Disease”, a Keystonesymposium, 2001. Faculty of 1000 contributor 2001-present (www.facultyof1000.com/start.asp).Selected peer-reviewed publications (in chronological order)Original Research/Peer-reviewed journals (from total of 75 original research publications)1. Gold, M.R., D.A. Law and A.L. DeFranco. (1990) Stimulation of protein tyrosinephosphorylation by the B lymphocyte antigen receptor. Nature 345: 810-813.2. Yu, C.C.K., T.S.B. Yen, C.A. Lowell, and A.L. DeFranco (2001). Lupus-like kidneydisease in mice deficient in Src-family protein tyrosine kinases Lyn and Fyn. Curr. Biol.11:34-38.3. Gupta, N., B. Wollscheid, J.D. Watts, B. Scheer, R. Aebersold, and A.L. DeFranco(2006). Quantitative proteomic analysis of B cell lipid rafts reveals that ezrin regulatesantigen receptor-mediated lipid raft dynamics. Nature Immunol. 7: 625-633.4. Mamchak, A.A., B.M. Sullivan, B. Hou, L.M. Lee, J.K. Gilden, M.F. Krummel, R.M.Locksley, and A.L. DeFranco (2008). Normal development and activation but alteredcytokine production of Fyn-deficient CD4+ T cells. J. Immunol. 181: 5374-5385.PMC26575555. Gross, A.J., J.R. Lyandres, A.K. Panigrahi, E.T.L. Prak, and A.L. DeFranco (2009).Developmental acquisition of the Lyn-CD22-SHP-1 inhibitory pathway promotes B Celltolerance. J. Immunol. 182: 5382-92. PMC28400416. Gross, A.J., I. Proekt, and A.L. DeFranco (2011). Elevated BCR signaling and decreasedsurvival of Lyn-deficient transitional and follicular B cells. Eur. J. Immunol. 41: 3645-3655. PMC in process.7. Hou, B., P. Saudan, G. Ott, M.L. Wheeler, M. Ji, L. Kuzmich, L.M. Lee, R.L. Coffman,M.F. Bachmann, A. L. DeFranco (2011). Selective utilization of Toll-like receptor andMyD88 signaling in B cells for enhancement of the anti-viral germinal center response.Immunity 34: 375-84. PMC3064721.8. Scapini, P., Lamagna, C., Hu, Y., Lee, K., Tang, Q., DeFranco, A. L., Lowell, C.A.(2011) B cell-derived IL-10 suppresses inflammatory disease in Lyn-deficient mice.Proc. Natl. Acad Sci. 108: E823-832. PMC31931939. Wheeler, M.L., and A.L. DeFranco (2012). Prolonged production of reactive oxygenspecies in response to BCR stimulation promotes B cell activation and proliferation. J.Immunol. 189: 4405-16.10. Kirkland, D., A. Benson, J. Mirpuri, R. Pifer, B. Hou, A.L. DeFranco, F. Yarovinsky Bcell-intrinsic MyD88 signaling prevents the lethal dissemination of commensal bacteriaduring colonic damage (2012). Immunity 36: 228-238. PMC3288553.124

Additional recent publications of importance to the field (in chronological order)11. Nishiya, T. and A.L. DeFranco (2004). Ligand-regulated chimeric receptor approachreveals distinctive subcellular localization and signaling properties of the Toll-likereceptors. J. Biol. Chem. 279: 19008-19017.12. Nishiya, T. Kajita, E., Miwa, S. and A.L. DeFranco (2005). TLR3 and TLR7 aretargeted to the same intracellular compartments by distinct regulatory elements. J. Biol.Chem. 280: 37107-17.13. Hou, B., B. Reizis, and A.L. DeFranco (2008). Toll-like receptors activate innate andadaptive immunity using dendritic cell-dependent and -independent mechanisms.Immunity 29: 272-82. PMC284779614. Scapini, P., Y. Hu, C.L. Chu, T.S. Migone, A.L. DeFranco, M.A. Cassatella, and C.A.Lowell (2010). Myeloid cells, BAFF, and IFN-g establish an inflammatory loop thatexacerbates autoimmunity in Lyn-deficient mice. J. Exp. Med. 207:1757-73.PMC291612415. Hou, B., A. Benson, L. Kuzmich, A.L. DeFranco and F. Yarovinsky (2011). Criticalcoordination of innate immune defense against Toxoplasma gondii by dendritic cellsresponding via their Toll-like receptors. Proc. Natl. Acad. Sci. USA 108: 278-283.PMC3017180Research projects ongoing or completed during the last the three yearsActive1. “Regulation of B lymphocyte proliferation by antigen”Principal Investigator: Anthony DeFrancoAgency: National Institute for Allergy and Infectious DiseaseType: R01 (AI20038-26). Period: 12/1/05-11/30/10 (12/10-11/30/11 no cost extension)The major goals of this project are: 1. Define the roles of ezrin and non-muscle myosins inlipid raft coalescence following BCR stimulation. 2. Define the role of B144, Rho-familyGTPases, and non-muscle myosin motors in directing outgrowth of long membrane processesin BCR-stimulated B cells. 3. Determine the mechanism of assembly of the NF-kBsignalosome at lipid rafts in mature B cells stimulated through the BCR. 4. Characterize thedifferences between immature B cells and mature B cells with regard to BCR-induced lipidraft coalescence and assembly of the Carma1/Bcl10 signaling complex.2. “Cell Type-Specific Roles of TLR Signaling in Immune Responses”Principal Investigator: Anthony DeFrancoAgency: NIAIDType: R01 (R01AI0720585-3). Period: 12/1/07-11/30/2012The major goals of this project are: Aim 1: To define the role of TLR signaling in dendriticcells for initiating adaptive T cell immune responses. Aim 2: To define the role of TLRsignaling in phagocytic cells for inducing inflammation and promoting microbial killingduring bacterial infection. Aim 3: To define the role of TLR signaling in B lymphocytes foramplifying antibody responses.3. “Innate Immune Regulation of Inflammation and Adaptive Immunity”125

Program Director: Anthony L. DeFranco. Project #1 “Cellular Basis of TLR Signaling forMucosal Immune Responses” (A.L. DeFranco, PI)Agency: NIAIDType: P01 (AI078869-02). Period: 7/1/08-6/30/13The major goals of Project 1 are: Aim 1: To define the role of TLR signaling in dendriticcells for initiating adaptive T cell immune responses to antigen challenge via the airways.Aim 2: To define the role of TLR signaling in immature dendritic cells and in neutrophils andmacrophages for innate and adaptive immune responses to fungal cell walls. Aim 3: Todefine the role of TLR signaling in immature dendritic cells and in neutrophils andmacrophages for immune defense against systemic infection with the fungal pathogenCandida albicans.Completed (last 3 years)1. “Cytoskeleton and Signal Transduction in Host Defense”Principal Investigator: Anthony DeFranco Agency: NIAIDType: R01 (R01 AI35811-11). Period: 12/1/06-1/31/10The goals of this project are to characterize the functional alterations of L-plastin-deficiencyon neutrophil and T cell function (This grant was awarded to Dr. Eric Brown and I becamethe PI to finish the project when Dr. Brown took a position at Genentech, Inc.).126

BIOGRAPHICAL SKETCHNAMEDavid J. Erle, M.D.eRA COMMONS USER NAMEDJERLEPOSITION TITLEProfessor of MedicineEDUCATION/TRAININGINSTITUTION AND LOCATION DEGREE YEAR(s) FIELD OF STUDYHarvard College, Cambridge, MA A.B. 1980 BiochemistryUniversity of California, San Francisco, CA M.D. 1984 MedicineUniversity of California, San Francisco, CA Resident 1984-87 Internal MedicineUniversity of California, San Francisco, CA Fellow 1987-90 Pulmonary DiseasePositions1984-1987 Resident in Internal Medicine, University of California Hospitals,San Francisco1987-1988 Clinical Pulmonary Fellow, University of California Hospitals, San Francisco1988-1990 Research Fellow, Lung Biology Center and Cardiovascular ResearchInstitute, UCSF1990-1992 Adjunct Assistant Professor of Medicine, UCSF1990-present Attending Physician, San Francisco General Hospital1992-1998 Assistant Professor of Medicine in Residence, UCSF1996-present Faculty, UCSF Immunology and Biomedical Sciences Graduate Programs1997-2001 UCSF/SFGH General Clinical Research Center (GCRC) AdvisoryCommittee1998-2004 Associate Professor of Medicine, UCSF1999-present Investigator, Cardiovascular Research Institute, UCSF2000-present Director, Functional Genomics Core Facility, UCSF SABRE Center2004-present Professor of Medicine, UCSF2006-2011 Associate Director, UCSF Clinical and Translational Sciences InstituteBioinformatics ProgramHonors1977 Detur Prize1977, 1978 John Harvard Scholarship1984 Alpha Omega Alpha, elected1990-1993 Edward Livingston Trudeau Award of the American Lung Association2008-2012 Member, LCMI Study Section (chair 2010-2012)127

Selected peer-reviewed publicationsFifteen most relevant to my role as director of the SABRE Center Functional Genomics Core(all include microarray studies):1. Kuperman DA, Huang X, Koth LL, Chang GH, Dolganov GM, Zhu Z, Elias JA,Sheppard D, Erle DJ. Direct effects of interleukin-13 on epithelial cells cause airwayhyperreactivity and mucus overproduction in asthma. Nat Med 8:885-9, 2002. PMID:12091879.2. Barczak A, Rodriguez MW, Hanspers K, Koth LL, Tai YC, Bolstad BM, Speed TP, ErleDJ. Spotted long oligonucleotide arrays for human gene expression analysis. GenomeRes 13:1775-85, 2003. PMCID: PMC403751.3. Woodruff PG, Koth LL, Yang YH, Rodriguez MW, Favoreto S, Dolganov GM, PaquetAC, Erle DJ. A distinctive alveolar macrophage activation state induced by cigarettesmoking. Am J Respir Crit Care Med 172:1383-1392, 2005. PMCID: PMC2718436.4. Kuperman DA, Lewis CC, Woodruff PG, Rodriguez MW, Yang YH, Dolganov GM,Fahy JV, Erle DJ. Dissecting asthma using focused transgenic modeling and functionalgenomics. J Allergy Clin Immunol 116:305-11, 2005. PMID: 16083784.5. Woodruff PG, Boushey HA, Dolganov GM, Barker CS, Yang YH, Donnelly S,Ellwanger A, Sidhu SS, Dao-Pick TP, Pantoja C, Erle DJ, Yamamoto KR, Fahy JV.Genome-wide profiling identifies epithelial cell genes associated with asthma and withtreatment response to corticosteroids. Proc Natl Acad Sci USA 104:15858-63, 2007.PMCID: PMC2000427.6. Zhen G, Park SW, Nguyenvu LT, Rodriguez MW, Barbeau R, Paquet AC, Erle DJ.Interleukin-13 and EGF receptor have critical but distinct roles in epithelial cell mucinproduction. Am J Respir Cell Mol Biol 36(2):244-53, 2007. PMCID: PMC1899314.7. Lewis CC, Yang JY, Huang X, Banerjee SK, Blackburn MR, Baluk P, McDonald DM,Blackwell TS, Nagabhushanam V, Peters W, Voehringer D, Erle DJ. Disease-specificgene expression profiling in multiple models of lung disease. Am J Respir Crit Care Med177:376-87, 2008. PMCID: PMC2258439.8. Park SW, Verhaeghe C, Nguyenvu LT, Barbeau R, Eisley CJ, Nakagami Y, Huang X,Woodruff PG, Fahy JV, Erle DJ. Distinct roles of FOXA2 and FOXA3 in allergic airwaydisease and asthma. Am J Respir Crit Care Med 180:603-10, 2009. PMCID:PMC2753788.9. Park SW, Zhen G, Verhaeghe C, Nakagami Y, Nguyenvu LT, Barczak AJ, Killeen N,Erle DJ. The protein disulfide isomerase AGR2 is essential for production of intestinalmucus. Proc Natl Acad Sci USA 106:6950-52009, 2009. PMCID: PMC2678445.10. Wang BT, Ducker GS, Barczak AJ, Barbeau R, Erle DJ, Shokat KM. The mammaliantarget of rapamycin regulates cholesterol biosynthetic gene expression and exhibits arapamycin-resistant transcriptional profile. Proc Natl Acad Sci USA 108:15201-6, 2011.PMCID: PMC3174577.11. Zhao W, Blagev D, Pollack J, Erle DJ. Toward a systematic understanding of mRNA 3’untranslated regions. Proc Am Thorac Soc 8:163-6, 2011. PMCID: PMC3131834.12. Sugimoto K, Kudo M, Sundaram A, Ren X, Huang K, Bernstein X, Wang Y, RaymondWW, Erle DJ, Abrink M, Caughey GH, Huang X, Sheppard D. The αvβ6 integrinmodulates airway hyperresponsiveness in mice by regulating intraepithelial mast cells. JClin Invest 122:748-58, 2012. PMCID: PMC3266785.128

13. Diez D, Goto S, Fahy JV, Erle DJ, Woodruff PG, Wheelock ÅM, Wheelock CE.Network analysis identifies a putative role for the PPAR and type 1 interferon pathwaysin glucocorticoid actions in asthmatics. BMC Med Genomics 5:27, 2012. PMCID:PMC3408345.14. Schroeder BW, Verhaeghe C, Park SW, Nguyenvu LT, Huang X, Zhen G, Erle DJ.AGR2 is induced in asthma and promotes allergen-induced mucin overproduction. Am JRespir Cell Mol Biol 47:178-85, 2012. PMCID: PMC3423459.15. Solberg OD, Ostrin EJ, Love MI, Peng JC, Bhakta NR, Hou L, Nguyen C, Solon M,Nguyen C, Barczak AJ, Zlock LT, Blagev DP, Finkbeiner WE, Ansel KM, Arron JR,Erle DJ*, Woodruff PG*. Airway epithelial miRNA expression is altered in asthma. AmJ Respir Crit Care Med 2012 [Epub ahead of print] PubMed PMID: 22955319. * equalcontributions.Research SupportActiveR01 HL099101 (Erle) 01/01/2010-12/31/2013NIH/NHLBI $247,500Specialized Molecules with Essential Roles in Mucus ProductionThe major goals of this project are: 1) To analyze AGR2 and AGR3 substrate bindingspecificity. 2) To determine the in vivo roles of AGR2 and AGR3 in the mouse airway. 3) Toanalyze the functions of AGR2 and AGR3 in human airway epithelial cells.R21 HL108596 (Erle) 04/06/2011-03/31/2013NIH/NHLBI $125,000Micro-RNAs in airway epithelial differentiation and asthmaThe major goal of this project is to develop tools to determine how selected miRNAs affectairway epithelial cell differentiation and function.P01 HL108794 (PD: Sheppard) 08/09/2012-07/31/2017NIH/NHLBI $1,666,456Role: Co-InvestigatorProgram: Targeting Epithelial Cells to Treat Pulmonary FibrosisThis translational program project grant is designed to develop new effective therapies foridiopathic pulmonary fibrosis (IPF).PENDINGU19 AI 077439-06 (PD: Sheppard, Project 1 leader: Erle) 04/01/2013-03/31/2018NIH/NIAID Program: $1,086,097(priority score: 20, funding expected per NIH program officer) Project 1: $274,962Program: IL-13 and IL-17 dynamics in the asthmatic airwayProject 1: IL-13/17-regulated airway epithelial miRNAs in asthmaOverall project goal is to determine how immune cells producing IL-13 and IL-17 specificallymodulate contractile responses of airway smooth muscle and the relevance of these pathwaysto human asthma.129

CompletedR21 HG004665 (Erle) 04/01/08-03/31/10NIH/NHGRITools for high-throughput functional analysis of 3’ UTR cis-regulatory elementsThe major goals of this project were: 1) To optimize the design and implementation of the 3’UTR high-throughput reporter system. 2) To use the system to identify cis-regulatoryelements within a representative group of 3’ UTRs from ENCODE regions of the genome.UL1 RR024131 (PD: McCune) 09/30/06-06/30/11NIH/NCRRClinical and Translational Science InstituteRole on project: Co-investigatorThe overall mission of the CTSI is to create an integrated academic home that transformsresearch and education in clinical investigation and translational science at UCSF andthroughout the community. Dr. Erle is a member of the Bioinformatics unit of the CTSI,which supports clinical and translational research and training at UCSF.R01 HL085089 (Erle) 07/21/06-06/30/12NIH/NHLBIAirway Epithelial Responses to Allergic InflammationThe major goals of this project were: 1) To determine the role of the EGF receptor pathway inthe airway epithelial cell response to IL-13. 2) To determine the role of the transcription factorFOXA2 in the airway epithelial cell response to IL-13. 3) To determine how the IL-13-inducible epithelial anion exchanger SLC26A4 (Pendrin) contributes to allergic airwaydisease. 4) To determine how the IL-13-inducible goblet cell-specific secreted protein anteriorgradient 2 (AGR2) contributes to allergic airway disease.130

BIOGRAPHICAL SKETCHNAMEJohn Vincent Fahy, M.D., M.Sc.eRA COMMONS USER NAMEjohnfahyPOSITION TITLEProfessor of Medicine in ResidenceEDUCATION/TRAININGINSTITUTION AND LOCATION DEGREE YEAR(s) FIELD OF STUDYUniversity College Dublin MB BAO 1985 MedicineBCHUniversity College Dublin Intern 1985-1986 Medicine and SurgeryTrinity College Dublin Resident 1986-1989 Internal MedicineUniversity College Dublin Registrar 1988-1999 Respiratory MedicineUniversity of California, San Francisco Fellow 1989-1993 Pulmonary/CriticalCare MedicineUniversity College DublinTrinity College DublinPositionsInternship and ResidenciesM.D.(doctorate bythesis)M.Sc.1997 Respiratory Medicine2003(Sabbaticalyear)Molecular Medicine1985 - 1986 Medicine Intern, St Vincent’s Hospital, University College Dublin.1986 - 1988 Senior House Officer, St James’ Hospital, Trinity College Dublin.1988 - 1989 Medicine Registrar (pulmonary medicine), St Vincent’s Hospital, UniversityCollege Dublin.1989 - 1993 Fellow, Pulmonary and Critical Care Medicine, UCSF.Academic Appointments1993 - 1998 Assistant Adjunct Professor of Medicine, UCSF.1999 - 2005 Associate Professor of Medicine in Residence, UCSF.2005 - Present Professor of Medicine in Residence, UCSF.Other Experience and Professional Memberships1993 - Present Member, Steering Committee, NHLBI’s Asthma Clinical Research Network2005 - 2006 Member, Executive Planning Committee, NHLBI Strategic Plan2006 - Present Director, Airway Clinical Research Center, UCSF.2007 - Present Chair, Data and Safety Monitoring Board for Division of Lung DiseasesSCCOR Program2004 - Present Member, Program Committee, Asthma, Inflammation, and ImmunologyAssembly, ATS.131

2009 - 2010 Chair (elected), Program Committee, Asthma, Inflammation, & ImmunologyAssembly, ATS.2009 - Present Member, Trans NIH Asthma Outcomes Working Group.2010 - Present Member, Scientific Committee, Transatlantic Airway Conference.Honors1984 Kirwan Gold Medal and Prize in Ophthalmology, University College Dublin (UCD)1985 Graduated fifth in class of 120 students, UCD Medical School (one of 10 to receive anhonors degree).1990 Travelling Studentship in Medicine, National University of Ireland1994 Physician Scientist Award, American College of Chest Physicians.2006 Michael S. Stulbarg Endowed Chair in Pulmonary Medicine, UCSF.Selected Peer-reviewed Publications1. Ordoñez CL, Khashayar, R, Wong HH, Ferrando R, Wu R, Hyde DM, Hotchkiss JA, ZhangY, Novikov A, Dolganov G, Fahy JV. Mild and moderate asthma is associated with gobletcell hyperplasia and abnormalities in mucin gene expression. Am J Resp Crit Care Med2001;163:517-523.2. Hays SR, Woodruff PG, Khashayar R, Ferrando RE, Liu J, Fung P, Zhao CQ, Wong HH,Fahy JV. Allergen challenge causes inflammation but not goblet cell degranulation inasthmatic subjects. J Allergy Clin Immunol 2001;108:784-790.3. Woodruff PG, Boushey HA, Dolganov GM, Barker CS, Yang YH, Donnelly S, Ellwanger A,Sidhu S, Dao-Pick TP, Pantoja C, Erle DJ, Yamamoto KR, Fahy JV. Genome-wide profilingidentifies epithelial cell genes associated with asthma and with treatment response tocorticosteroids. Proc Natl Acad Sci USA 2007; 104:15858-63.4. Seibold MA, Donnelly S, Solon M, Innes A, Woodruff PG, Boot R, Burchard EG, Fahy JV.Chitotriosidase is the primary active chitinase in the human lung and is modulated bygenotype and disease. J Allergy Clin Immunol. 2008;122:944-950. PMCID: PMC2666777.5. Innes AL. Carrington SD, David J. Thornton DJ, Kirkham S, Dougherty RH, Raymond WW,Caughey GH, Muller SJ, Fahy JV. Ex vivo sputum analysis reveals impairment of proteasedependentmucus degradation by plasma proteins in acute asthma. Am J Respir Crit CareMed. 2009;180:203-10. PMCID: PMC2724713.6. Woodruff PG, Modrek M, Choy DF, Guiquan J. Abbas AR, Ellwanger A, Koth LL, ArronJR, Fahy JV. TH2-driven inflammation defines major sub-phenotypes of asthma. Am JRespir Crit Care Med. 2009;180:388-95.7. Seibold MA, Reese TA, Choudhry S, Salam MT, Beckman K, Eng C, Atakilit A, Meade K,Lenoir M, Watson HG, Thyne S, Kumar R, Weiss KB, Grammer LC, Avila P, Schleimer RP,Fahy JV, Rodriguez-Santana J, Rodriguez-Cintron W, Boot RG, Sheppard D, Gilliland FD,Locksley RM, Burchard EG. Differential enzymatic activity of common haplotypic versionsof the human acidic mammalian chitinase protein. J Biol Chem 2009;284:19650-8.8. Dougherty RH, Sidhu SS, Raman K, Solon M, Solberg OD, Caughey GH, Woodruff PG,Fahy JV. Accumulation of Intra-epithelial Mast Cells with a Unique Protease Phenotype inTH2-high Asthma. J Allergy Clin Immunol. 2010;125:1046-1053.9. Sukhvinder SS, Yuan S, Innes AL, Kerr S, Woodruff PG, Solon M, Hou L, Muller SL, FahyJV. Epithelial cell-derived periostin: roles in TGFβ activation, collagen production andcollagen elasticity in asthma. Proc Natl Acad Sci USA. 2010;107:14170-5.132

10. Fahy JV, Dickey B. Airway Mucus - Function and Dysfunction. New Engl J of Med. 2010;2;363:2233-47.11. Innes AL, Wong McGrath K, Dougherty RH, McCulloch CE, Woodruff PG, Seibold MA,Okamoto KS, Kelsey J. Ingmundson KJ, Solon MC, Carrington SD, Fahy JV. The H Antigenat Epithelial Surfaces is Associated with Susceptibility to Asthma Exacerbation. Am J RespirCrit Care Med. 2011;183:189-94.12. Choy DF, Modrek B, Abbas AR, Kummerfeld S, Clark HF, Wu LC, Fedorowicz G,Modrusan Z, Fahy JV, Woodruff PG, Arron JR. Gene expression patterns of TH2inflammation and intercellular communication in asthmatic airways. J Immunol.2011;186:1861-9.13. Fahy JV, Locksley RM, The airway epithelium as a regulator of TH2 responses in asthma.American Journal of Respiratory and Critical Care Medicine 2011;184: 390-392.14. Gordon ED, Sidhu SS, Wang ZE, Woodruff PG, Yuan S, Solon MC, Conway SJ, Huang X,Locksley RM, Fahy JV. A protective role for periostin and TGFβ in IgE-mediated allergyand airway hyperresponsiveness. Clinical and Experimental Allergy 2012;42:144-55.15. Wong McGrath K, Icitovic N, Boushey HA, Lazarus SC, Sutherland, ER, Chinchilli VM,Fahy JV. A large subgroup of mild moderate asthma is persistently non-eosinophilic.American Journal of Respiratory and Critical Care Medicine. 2012; 185(6):612-9.Research Support1P01HL107202 (Fahy, JV) 8/1/12 - 6/30/17Innate and Adaptive Immune Responses in Th2-high AsthmaThis PPG will comprehensively investigate the molecular underpinnings of the Th2-highmolecular subtype of asthmaRole: Overall PPG PI (Project leader for project 3 and Core leader for the Administrative Coreand the Human Subjects Core.1U10HL109146 (Fahy JV) 8/1/2011-7/31/2017Clinical and Molecular Phenotypes of Severe AsthmaThis grant was submitted in response to the RFA for Clinical Centers for the Severe AsthmaResearch program) – a 6-center national program for research into mechanisms of severe asthma.Role: PI5 R01 HL080414 (Fahy, JV) 7/01/05-05/31/15Protein carbohydrate interactions in the pathophysiology of acute asthma exacerbationsThe major goals of this project are to investigate how lectins interact with mucin glycans tocause airway mucus obstruction in acute severe asthma.Role: PI1P50HL107191 (Fahy, JV) 5/01/11-04/30/13Preventing fucose-dependent binding of aspergillus and pseudomonas to lung mucinThis grant was submitted in response to the RFA for “Centers for Advanced Diagnostics andExperimental Therapeutics (CADET-1)”.Role: PI133

1 U19 A1077439 (Sheppard, D) 4/01/08-3/31/13NIH/NIAIDMechanisms of Initiation & Persistence of Allergic Asthma; Project 3: Chitinases and TGFβ inhuman asthma.The goal of this center grant is to examine the role of chitinases and TGFβ pathway genes inasthma. Project 3 specifically focuses on genetic and translational studies of chitinases & TGFβin asthma.Role: Co-Leader of Project 3 (with Esteban Burchard, M.D.)1 R01 HL097591 (Woodruff, PG) 7/01/09-06/30/13NIH/NHLBIRole of Th2 and non-Th2 Inflammation in Airway Smooth Muscle Remodeling in Asthma.This grant supports studies of airway smooth muscle in asthma.Role: Co-investigator134

BIOGRAPHICAL SKETCHNAMEXiaozhu Huang, M.D.POSITION TITLEAssociate ProfessorEDUCATIONINSTITUTION AND LOCATION DEGREE YEAR FIELD OF STUDYTongji Medical University, Wuhan,People's Republic of ChinaTongji Medical University, Wuhan,People's Republic of ChinaM.D. 1983 MedicineM.S. 1988 PathologyPositions6/83 to 7/84 Teaching Assistant, Dept. of Pathology, Tongji Medical University, China8/84 to 8/85 Pathology Residence, The First Attached Hospital, Tongji Medical University,China9/88 to 1/92 Research Assistant, Dept. of Pathology, Tongji Medical University, China1/92 to 12/95 Postdoctoral Fellow, Dept. of Medicine, Lung Biology CenterUniversity of California, San Francisco1/96 to 6/97 Postgraduate Researcher, Dept. of Medicine, Lung Biology CenterUniversity of California, San Francisco7/97 to 11/99 Assistant Research Molecular Biologist, Dept. of Medicine, Lung BiologyCenterUniversity of California, San Francisco12/99 to 6/2005 Assistant Professor, Dept. of Medicine, Lung Biology CenterUniversity of California, San Francisco07/2005 to present Associate Professor, Dept. of Medicine, Lung Biology CenterUniversity of California, San FranciscoHonors1989 "Outstanding Teacher" Honor, Department of Pathology,Tongji Medical University1/1992 to 12/1993 Cheng Research Scholar Award,135

Selected peer-reviewed publications1. Huang XZ, Chen A, Agrez M, Sheppard D. A point mutation in integrin b6 subunitabolishes both avb6 binding to fibronectin and receptor localization to focal adhesionplaques. Am. J. Respir. Cell Mol. Biol. 1995; 13:245-251.2. Huang XZ, Wu JF, Cass D, Erle DJ, Corry D, Young SG, Farese RV, Jr., SheppardD. Inactivation of the integrin b6 subunit gene reveals a role of epithelial integrins inregulating inflammation in the lungs and skin. J. Cell Biol. 1996; 133:921-928.3. Huang XZ, Wu JF, Zhu W, Pytela R, Sheppard D. Expression of the human integrinb6 subunit in alveolar type II cells and bronchiolar epithelial cells reverses lunginflammation in b6 knockout mice. Am. J. Respir. Cell Mol. Biol. 1998; 19:636-642.4. Huang XZ, Wu JF, Spong S, Sheppard D. The integrin avb6 is critical forkeratinocyte migration on both its known ligand, fibronectin, and on vitronectin. J.Cell Sci. 1998; 111:2189-2195.5. JS Munger, XZ Huang, H Kawakatsu, MJD Griffiths, SL Dalton, JF Wu, JF Pittet, NKaminiski, C Garat, MA Matthay, DB Rifkin, D Sheppard. The integrin avb6 bindsand activates latent TGFb1: a mechanism for regulating pulmonary inflammation andfibrosis. Cell 1999; 96:319-328.6. Milner R, Huang XZ, Wu J, Nishimura S, Pytela R, Sheppard D, ffrench-ConstantC. Distinct roles for astrocyte avb5 and avb8 integrins in adhesion and migration. J.Cell Sci. 1999; 112: 4271-4279.7. Huang XZ, Griffiths M, Wu JF, Farese RV, Sheppard D. Normal development,wound healing, and adenovirus susceptibility in b5-deficient mice. Mol. Cell Biol.2000; 20:755-759.8. Kaminski N, Allard J, Pittet J-F, Zuo F, Griffiths MJD, Morris D, Huang XZ,Sheppard D, Heller RA. Global analysis of gene expression in pulmonary fibrosisreveals distinct programs regulating lung inflammation and remodeling. Proc. Nat.Acad. Sci. 2000; 97:1778-1783.9. Huang XZ, Wu JF, Ferrando R, Wang YL, Lee JH, Farese RV, Sheppard D. FatalBilateral Chylothorax in Mice Lacking the Integrin a9b1. Mol. Cell Biol. 2000;20:5208-5215.10. Pittet JF, Griffiths MJ, Geiser T, Kaminski N, Dalton SL, Huang XZ, Brown LA,Gotwals PJ, Koteliansky VE, Matthay MA, Sheppard D. TGF-beta is a criticalmediator of acute lung injury. J Clin Invest. 2001, 107:1537-44.11. Reynolds LE, Wyder L, Lively JC, Taverna D, Robinson SD, Huang XZ, SheppardD, Hynes RO, Hodivala-Dilke KM. Enhanced pathological angiogenesis in micelacking beta3 integrin or beta3 and beta5 integrins. Nat Med. 2002, 8:27-34.12. Eliceiri BP, Puente XS, Hood JD, Stupack DG, Schlaepfer DD, Huang XZ,Sheppard D, Cheresh DA. Src-mediated coupling of focal adhesion kinase to integrinalpha(v)beta5 in vascular endothelial growth factor signaling. J Cell Biol. 2002,157:149-60.13. Kuperman DA, Huang XZ, Koth LL, Chang GH, Dolganov GM, Zhu Z, Elias JA,Sheppard D, Erle DJ. Direct effects of interleukin-13 on epithelial cells cause airwayhyperreactivity and mucus overproduction in asthma. Nat Med. 2002, 8:885-9.14. Knight PA, Wright SH, Brown JK, Huang XZ, Sheppard D, Miller HR. Entericexpression of the integrin alpha(v)beta(6) is essential for nematode-induced mucosalmast cell hyperplasia and expression of the granule chymase, mouse mast cellprotease-1. Am J Pathol. 2002, 161:771-9.15. Morris DG, Huang XZ, Kaminski N, Wang Y, Shapiro SD, Dolganov G, Glick A,Sheppard D. Loss of integrin-mediated TGF-b activation causes Mmp12-dependent136

pulmonary emphysema. Nature 2003, 422:169-73.16. Nandrot EF, Kim Y, Brodie SE, Huang XZ, Sheppard D, Finnemann SC. Loss ofsynchronized RPE phagocytosis and age-related blindness in mice lacking avb5integrin. J Exp Med. 2004, 200:1539-45.17. Lane NE, Yao W, Nakamura MC, Humphrey MB, Kimmel D, Huang XZ, Sheppard,Ross FP, Teitelbaum SL. Mice lacking the integrin beta5 subunit have acceleratedosteoclast maturation and increased activity in the estrogen-deficient state. J BoneMiner Res. 2005, 20:58-66.18. Kuperman DA, Huang XZ, Nguyenvu L, Hölscher C, Brombacher F, Erle DJ. IL-4receptor signaling in Clara cells is required for allergen-induced mucus production. J.Immunol. 2005, 175:3746-3752.19. Atabai K, Fernandez R, Huang X, Ueki I, Kline A, Li Y, Sadatmansoori S, Smith-Steinhart C, Zhu W, Pytela R, Werb Z, Sheppard D. Mfge8 Is Critical for MammaryGland Remodeling during Involution. Mol Biol Cell. 2005, 16:5528-37.20. Voehringer D, Reese TA, Huang X, Shinkai K, Locksley RM. Type 2 immunity iscontrolled by IL-4/IL-13 expression in hematopoietic non-eosinophil cells of theinnate immune system. J Exp Med. 2006, 203:1435-46.21. Wang B, Huang X*, Wolters PJ, Sun J, Kitamoto S, Yang M, Riese R, Leng L,Chapman H A., Finn P W., David J R., Bucala R, and Shi GP. Deficiency ofMacrophage Migration Inhibitory Factor Impairs Murine Airway Allergic Responses.J Immunol 2006, 177:5779-5784 (* Co-first author)22. Chen C, Huang X, Sheppard D. ADAM33 is not essential for growth anddevelopment and does not modulate allergic asthma in mice. Mol Cell Biol. 2006,26:6950-6.23. Chen C, Huang X, Atakilit A, Zhu QS, Corey SJ, Sheppard D. The Integrinalpha9beta1 Contributes to Granulopoiesis by Enhancing Granulocyte Colony-Stimulating Factor Receptor Signaling. Immunity. 2006, 25:895-906.24. Su G, Hodnett M, Wu N, Atakilit A, Kosinski C, Godzich M, Huang XZ, Kim JK,Frank JA, Matthay MA, Sheppard D, Pittet JF. Integrin {alpha}v{beta}5 RegulatesLung Vascular Permeability and Pulmonary Endothelial Barrier Function. Am JRespir Cell Mol Biol. 2007, 36:377-86.25. Travis MA, Reizis B, Melton AC Masteller E, Tang Q, Proctor J, Wang Y, BernsteinX, Huang X, Riechardt L, Bluestone J, Sheppard D. Loss of integrin avb8 ondendritic cells causes autoimmunity and colitis in mice. Nature 2007; 449:361-365.26. Horan GS, Wood S, Ona V, Li DJ, Lukashev ME, Weinreb PH, Simon KJ, Hahm K,Allaire NE, Rinaldi NJ, Goyal J, Feghali-Bostwick CA, Matteson EL, O'hara C,Lafyatis R, Davis GS, Huang X, Sheppard D, Violette SM. Partial Inhibition ofIntegrin {alpha}v{beta}6 Prevents Pulmonary Fibrosis Without ExacerbatingInflammation. Am J Respir Crit Care Med 2008; 177:56-65.27. Nakagami Y, Favoreto S Jr, Zhen G, Park SW, Nguyenvu LT, Kuperman DA,Dolganov GM, Huang X, Boushey HA, Avila PC, Erle DJ. The epithelial aniontransporter pendrin is induced by allergy and rhinovirus infection, regulates airwaysurface liquid, and increases airway reactivity and inflammation in an asthma model.J Immunol. 2008 Aug 1;181(3):2203-10.28. Song Y, Pittet JF, Huang X, He H, Lynch SV, Violette SM, Weinreb PH, Horan GS,Carmago A, Sawa Y, Bernstein XL, Wiener-Kronish JP. Role of integrin alphavbeta6 in acute lung injury induced by Pseudomonas aeruginosa. Infect Immun. 2008Jun;76(6):2325-3229. Caceres AI, Brackmann M, Elia MD, Bessac BF, del Camino D, D'Amours M, WitekJS, Fanger CM, Chong JA, Hayward NJ, Homer RJ, Cohn L, Huang X, Moran MM,Jordt SE.A sensory neuronal ion channel essential for airway inflammation and137

hyperreactivity in asthma.Proc Natl Acad Sci U S A. 2009 Jun 2;106(22):9099-104.30. Park SW, Verhaeghe C, Nguyenvu LT, Barbeau R, Eisley CJ, Nakagami Y, HuangX, Woodruff PG, Fahy JV, Erle DJ. Distinct Roles of FOXA2 and FOXA3 inAllergic Airway Disease and Asthma. Am J Respir Crit Care Med. 2009 Jul 23.31. Huang F, Rock JR, Harfe BD, Cheng T, Huang X, Jan YN, Jan LY. Studies onexpression and function of the TMEM16A calcium-activated chloride channel. ProcNatl Acad Sci U S A. 2009 Dec 15;106(50):21413-832. Frank Kirstein, Horsnell G William, Douglas A Kuperman, Xiaozhu Huang, David JErle, Andreas L Lopata, Frank Brombacher, Expression of IL-4 Receptor alpha onsmooth muscle cells is not necessary for development of experimental allergicasthma. J Allergy Clin Immunol. 2010 Aug;126(2):347-35433. Li, S. , Chen, Y. , Zhang, S. , More, S.S. , Huang, X. , Giacomini, K.M. Role ofOrganic Cation Transporter 1, OCT1 in the Pharmacokinetics and Toxicity of cisDiammine(pyridine)chloroplatinum(II) and Oxaliplatin in Mice. Pharm Res. 2010Nov 2334. Yu Hua Chow, Xiao Dong Zhu, Li Liu, Barbara Schwartz, Xiaozhu Huang, JohnHarlan, Lynn M Schnapp. Role of Cdk4 in lymphocyte function and allergenresponse. Cell Cycle. 2010 Dec 15;9(24):4922-3035. Masuno K, Haldar SM, Jeyaraj D, Mailloux C, Huang X, Panettieri Jr RA, Jain MK,Gerber AN. Expression Profiling Identifies Klf15 as a Glucocorticoid Target thatRegulates Airway Hyperresponsiveness. Am J Respir Cell Mol Biol. 2011 Jan 2136. Kudo M, Melton AC, Chen C, Engler MB, Huang KE, Ren X, Wang Y, Bernstein X,Li JT, Atabai K, Huang X*, Sheppard D. IL-17A produced by αβ T cells drivesairway hyper-responsiveness in mice and enhances mouse and human airway smoothmuscle contraction. Nat Med. 2012 Mar 4;18(4):547-54 (*co-authorship)37. Vijayanand P, Seumois G, Simpson LJ, Abdul-Wajid S, Baumjohann D, Panduro M,Huang X, Interlandi J, Djuretic IM, Brown DR, Sharpe AH, Rao A, Ansel KM.Interleukin-4 production by follicular helper T cells requires the conserved Il4enhancer hypersensitivity site V. Immunity. 2012 Feb 24;36(2):175-8738. Thornton E, Looney M, Sheppard D, Locksley R, Huang X, Krummel M. Dynamicsof antigen capture and presentation revealed by two-photon live imaging in the lung.J Exp Med. 2012 Jun 4;209(6):1183-9939. Schroeder BW, Verhaeghe C, Park SW, Nguyenvu LT, Huang X, Zhen G, Erle DJ.AGR2 is Induced in Asthma and Promotes Allergen-Induced Mucin Overproduction.Am J Respir Cell Mol Biol. 2012 Aug;47(2):178-8540. Bhattacharya M, Su G, Su X, Oses-Prieto JA, Li JT, Huang X, Hernandez H,Atakilit A, Burlingame AL, Matthay MA, Sheppard D. IQGAP1 is necessary forpulmonary vascular barrier protection in murine acute lung injury and pneumonia. AmJ Physiol Lung Cell Mol Physiol. 2012 Jul 1;303(1):L12-941. Chun Chen, Makoto Kudo, Florentine Rutaganira, Hiromi Takano, Candace Lee,Amha Atakilit, Toshimitsu Uede, Paul Wolters, Stephen Liggett, Kevan M. Shokat,Xiaozhu Huang and Dean Sheppard . Integrin α9β1 in airway smooth muscleregulates a novel brake on exaggerated murine and human airway narrowing. JCI2012 Aug 1;122(8):2916-2742. Huang F, Zhang H, Wu M, Yang H, Kudo M, Peters CJ, Woodruff PG, Solberg OD,Donne ML, Huang X, Sheppard, Fahy JV, Wolters PJ, Hogan BL, Finkbeiner WE, LiM, Jan YN, Jan LY, Rock JR. Calcium-activated chloride channel TMEM16Amodulates mucin secretion and airway smooth muscle contraction. Proc Natl AcadSci U S A. 2012 Oct 2;109(40):16354-9.43. Julia Freimuth, Frederic F. Clermont, Xiaozhu Huang, Angela De Sapio, TakuTokuyasu, Dean Sheppard, Rosemary J. Akhurst. Epistatic interactions between138

Tgfb1 and genetic loci, Tgfbm2 and Tgfbm3, determine susceptibility to an asthmaticstimulus. Proc Natl Acad Sci U S A. 2012 Oct 30;109(44):18042-744. Kudo M, Khalifeh Soltani SM, Sakuma SA, McKleroy W, Lee TH, Woodruff PG,Lee JW, Huang K, Chen C, Arjomandi M, Huang X, Atabai K. Mfge8 suppressesairway hyperresponsiveness in asthma by regulating smooth muscle contraction. ProcNatl Acad Sci U S A. 2013 Jan 8;110(2):660*Equal contribution139

BIOGRAPHICAL SKETCHNAMEMatthew Frederick Krummel, Ph.DeRA COMMONS USER NAMEKrummelPOSITION TITLEAssociate ProfessorEDUCATION/TRAININGINSTITUTION AND LOCATION DEGREE YEAR(s)FIELD OFSTUDYUniversity of Illinois at Champaign-Urbana B.S. 1989Biology andChemistryUniversity of California at Berkeley Ph.D. 1995 ImmunologyWalter and Eliza Hall Institute, MelbourneAustralia1996-1997 ImmunologyStanford University 1997-2001 ImmunologyPositionsSummer 1987Summer 1988Summer Undergraduate Research Fellow, UTHSCDStagiare (Technician) Institut Pasteur, Paris,Unite de Genie Micro-Biologique.1989-1996 Graduate Student and Postdoctoral Fellow, University of California atBerkeley, Department of Molecular and Cell Biology1996-1997 Postdoctoral Fellow, Walter and Eliza Hall Institute, MelbourneAustralia1997-2001 Postdoctoral Fellow, Beckman Institute, Stanford University, Stanford,CA2001-2006 Assistant Professor, Department of Pathology, UCSFJuly 2006-Present2006-Present2012-PresentHonorsAssociate Professor, Department of Pathology, UCSFFaculty Director, Biological Imaging Development Center, UCSFProfessor, Department of Pathology, University of California atSan Francisco2009-2012 Fellow of the American Asthma Foundation2005-2010 Leukemia and Lymphoma Foundation, Career Award2004-2007 Investigator Award, Cancer Research Institute.1997-2000 NRSA Postdoctoral Fellowship, National Institutes of Health1996-1997 Postdoctoral Fellowship, Juvenile Diabetes Foundation International140

1998 PATENT: J.P.Allison, D.R.Leach, and M.F. Krummel.Blockade of T Lymphocyte Down-Regulation Associated withCTLA-4 Signaling. US Patent 5,811,0971987 Summer Undergraduate Research Fellowship, Howard HughesMedical InstituteSelected Peer-reviewed Publications (out of 51)1. Krummel MF and Allison JP. 1995. CD28 and CTLA-4 have opposing signalswhich regulate the response of T cells to stimulation. J. Exp Med. 182, 459-465.PMCID: PMC21921272. Krummel MF, Sullivan TJ and Allison JP. 1995. Superantigen responses andcostimulation: CD28 and CTLA-4 have opposing effects on T cell expansion InVitro and In Vivo. Int.Immunol. 8, 101-105. PMCID: 86716383. Krummel MF and Allison JP. 1996. CTLA-4 Engagement Inhibits IL-2Accumulation and Cell Cycle Progression Upon Activation of Resting T cells. JExp Med 183, 2533-2540. PMCID: PMC21926134. Leach, D.R., Krummel MF and Allison JP. 1996. Enhancement of antitumorimmunity by CTLA-4 blockade. Science. 271, 1734-1736. PMID: 85969365. Krummel MF, Sjaastad MD, Wülfing C and Davis MM. 2000. Differentialclustering of CD4 and CD3z during T cell recognition. Science. 289, 1349-1352.PMID: 109587816. Jacobelli J, Chmura SA, Buxton DB, Davis MM and Krummel MF. 2004. Asingle class II myosin modulates T cell motility and stopping, but not synapseassembly. Nature Immunology 5, 531 – 538. PMCID: 150647617. Friedman RS Jacobelli J and Krummel MF. 2006. Surface-bound ChemokinesCapture and Prime T cells For Synapse Formation. Nature Immunology 7, 1101-8.PMID: 169642618. Sabatos CA, Doh J, Chakravarti S, Friedman RS, Pandurangi PG, Tooley AJ,Krummel, MF. 2008. A Synaptic Basis for Paracrine Interleukin-2 Signaling inActivating T cells. Immunity. 29(3): 238-248. PMID: 186749349. Tooley AJ, Gilden J, Jacobelli J, Trimble W, Kinoshita M and Krummel MF.2009. Amoeboid T lymphocytes require the septin cytoskeleton for corticalintegrity and persistent motility. Nature Cell Biology. Jan;11(1):17-26. Epub 2008Nov 30. PMID: 1904340810. Jacobelli J, Friedman RS, Conti MA, Lennon-Dumenil AM, Piel M, SorensenCM, Adelstein RS, Krummel MF. Confinement-optimized three-dimensional Tcell amoeboid motility is modulated via myosin IIA-regulated adhesions. NatImmunol. 11: 953-961. PMCID: PMC294356411. Friedman RS, Beemiller P, Sorensen CM, Jacobelli J, Krummel MF. 2010. Realtimeanalysis of T cell receptors in naive cells in vitro and in vivo revealsflexibility in synapse and signaling dynamics. J Exp Med. 11(10):953-61.PMCID: PMC298976612. Looney MR, Thornton EE, Sen D, Lamm WJ, Glenny RW, Krummel MF. 2011.Stabilized Imaging of immune surveillance in the mouse lung. Nat Methods.8(1):91-6. PMCID: PMC307600513. Englehardt JE, Boldajipour B, Beemiller P, Werb Z, Pandurangi P, Sorenson C,Egelblad M, Krummel MF. Marginating dendritic cells of the tumormicroenvironment cross-present tumor antigens and stably engage tumor-specificT cells. Cancer Cell. 2012 Mar 20;21(3):402-17. doi: 10.1016/j.ccr.2012.01.008.PMCID: PMC3311997

14. Thornton EE, Krummel MF, Looney, M.R. 2012. Live Imaging of the Lung. CurrProtoc Cytom. Apr; Chapter 12:Unit12.28.15. Thornton EE, Looney MR, Bose O, Sen D, Sheppard D, Locksley R, Huang X,Krummel MF. 2012. Spatiotemporally Separated Antigen Uptake by Alveolar DendriticCells and Airway Presentation to T Cells in the Lung. J Exp Med., 209(6):1183-99.Research supportOngoing Research Support1U01HL111054-01 (Chapman, Chuang, 01/01/12-12/31/16Krummel, multi-PI) (co-PI)NIHEpithelial Progenitor Cells in Lung Repair and Regeneration: Note: Scored 20 at study sectionThe goal of this project is to image the process of lung repair and regeneration using 2-photonmicroscopy.Role: co-PI1U01CA141451 (PI: Krummel) 09/01/09-08/31/14NIHCollaborative Innate-Adaptive Immune Regulation of Tumor ProgressionThe major goals of this project areGoal 1: Visualize the progression in crosstalk between the innate and adaptive immune responseduring tumor development using mouse models of luminal and basal breast cancer.Goal 2: Define the specific attractants that regulate immune cell-cell interactions in the tumor.Goal 3: Use mouse models to determine mechanisms of existing and putative immuno- andcytotoxic anti-cancer regimens and to design and test combinatorial therapies based upon thisinformation.Role: co-PIP01 HL024136 (PI: Caughey) 05/11/10-03/31/14NIH/NHLBIEvolving Microenvironments in Airway InflammationThe aims of this proposal are to identify shifts in antigen-trafficking into APC, the temporalpairing of specific APC with T cell subsets, and the effects of Mycoplasma-mediatedinflammation and mast-cell-mediated regulation upon T cell-APC pairing in lungmicroenvironments.Role: co-PIP01 HL024136 (PI: Caughey) 05/11/10-03/31/14Core BThis Core supports the basic activities of the PPG.Role: co-PI142

1R21CA167601 (PI) 05/01/12-03/31/14NIH/NCIDefining the First Hours of Lung metastasis using Intravital Live-ImagingThis proposal will apply novel intravital imaging of the lung to define the first hours followingthe arrival of metastatic cells into the mouse lung. As we know very little about why metastatictumor cells survive in this environment, this represents a major undertaking in determining howto decrease their success.Role: PIR01AI052116 (PI: Krummel) 01/15/12-12/31/17NIHMyosin Motors in T cell Synapse Formation and ActivationThe major goals of this project are to analyze MyoIIA regulation during T cell motilityand synapse formation. This includes mutational analyses as well as generation andanalyses of knockout animals.Role: PIU54 CA163123-01 (Coussens, Krummel, 09/1/12-08/30/13Van't Veer: multi-PI) (PI (MPI))NIH/NCILeukocyte Biomarkers for Predicting Human Breast Cancer OutcomeThe goal of this project is to identify predictive biomarkers in human breast cancer, using genomicprofiling of mouse and human breast cancer infiltrates and correlated analyses of outcome.Role: PI1R21CA167415-01 (PI) 05/01/12-04/30/14NIH/NCIPhage-Display Technology to Define and Manipulate Breast Tumor StromaThis proposal will utilize rapid phage-display screening methods to identify novel epitopeson tumor stromal cells. Through a rapid evolution and Fc-tagging method, both diagnosticand therapeutic uses of these reagents will be assessed. This will provide a rapid pipelinebetween identification of key cell types and their characterization and targeting.Role: PICompleted Research SupportR01 CA134622 ARRA (PI: Krummel) 07/17/09-06/30/11NIHRegulation of T cell Functions by the Breast Cancer MicroenvironmentThe major goals of this project areAim 1: Define the Nature of the CD8+ T cell response in the microenvironment of aSpontaneous Breast Tumor.143

Aim 2: Define the Nature of Tumor Sampling APCs (TSAPCs), the phenotype and capacity ofthese cells to activate T cells, and the changes in this population with addition of functionalCD8+ T cells.Aim 3: Define the effects of CD4 +T cell subsets, particularly regulatory cells, on CD8 activityin vivo and upon the quantity and phenotype of TSAPCs.Role: PIFellowship (PI: Krummel) 07/01/05-06/30/10Leukemia & Lymphoma SocietyTumor Suppressors in T cell Synapse Formation and SignalingThe major goals of this project areAim 1. We will determine the role of Septin9/MSF in T cell synapse development, signaling, andproliferative control.Aim 2. We will determine the role of lgl proteins in T cell synapse development, signaling, andproliferative control.Role: PIAAF Fellow (PI: Krummel) 07/01/09-06/30/12American Asthma FoundationDirecting Antigens to Specific APC and T cell subsets in the LungThe major goals of this project are to screen for conditions that bias antigens towards particularantigen presenting cell populations and then to read out, through imaging and functionalassays, the resulting T cell responses with the aim of optimizing regulatory interactionpathways.Role: PI144

BIOGRAPHICAL SKETCHNAMELimin Liu, Ph.D.eRA COMMONS USER NAMELIMINLIUPOSITION TITLEAssociate ProfessorEDUCATION/TRAININGINSTITUTION AND LOCATION DEGREE YEAR(s) FIELD OF STUDYUniversity of Science & Technology of China B.S. 1986 BiologyUniversity of Missouri, Columbia, MO Ph.D. 1995 Molecular BiologyDuke University Medical CenterNitric Oxide BiologyPositions1996- 1997 Research Associate, Department of Animal Sciences, University ofMissouri-Columbia1997- 2004 Research Associate, Department of Medicine, Division of Pulmonary Medicine,Duke University Medical Center1998-2003 Research Associate, Howard Hughes Medical Institute, Duke University MedicalCenter2005-2012 Assistant Professor, Sandler Center for Basic Research in Asthma, Department ofMicrobiology and Immunology, University of California San Francisco2012-Present Associate Professor, Sandler Center for Basic Research in Asthma, Department ofMicrobiology and Immunology, University of California San FranciscoHonors1989-1990 Scholarship, Division of Biological Sciences, University of Missouri1989-1993 Predoctoral Fellowship, Molecular Biology Program, University of Missouri1994 New Investigator Award (First Place), Society for the Study of Reproduction(Biology of Reproduction, Vol. 52, pp. 261)2005 Stewart Trust Cancer Research Award2006 Sandler Innovative Research AwardSelected peer-reviewed publications (in chronological order)1. Wu WY, Zhao YG and Liu L (1989). Trophic effect of slow nerve on minced fast musclefrom newly hatched chicks transplanted into three-week chicks. Chin J Physiol Sci 5:95-97.145

2. Wu WY, Zhao YG, Liu L, Lu DX and Tian, WH (1990). The second stage commitment ofchick muscle satellite cells and its relation to the state of innervation. Chin J Physiol Sci6:19-29.3. Roberts RM and Liu L (1996). Interferon-ω. In: Aggarawal BB and Gutterman U, eds.,Human Cytokines: Handbook for Basic and Clinical Research (II), pp.168-177.4. Liu L, Leaman DW, Bixby JA and Roberts RM (1996). A type 1 ovine interferon withlimited similarity to IFN-α, IFN-ω, and IFN-τ: gene structure, biological properties andunusual species specificity. Biochem Biophys Acta 1294:55-62.5. Liu L and Roberts RM (1996). Silencing of the gene for the β-subunit of human chorionicgonadotropin by the embryonic transcription factor Oct-3/4. J Biol Chem 271:16683-16689.6. Liu L, Leaman DW and Roberts RM (1996). The interferon-tau genes of the giraffe, anonbovid species. J Interferon Cytokine Res 16:949-951.7. Roberts RM, Liu L and Alexenko A (1997). New and atypical families of type I interferonsin mammals: comparative functions, structures and evolutionary relationships. Prog NucleicAcid Res Mol Biol 56:287-325.8. Liu L, Leaman DW, Villalta M and Roberts RM (1997). Silencing of the gene for thealpha-subunit of human chorionic gonadotropin by the embryonic transcription factorOct-3/4. Mol Endocrinol 11:1651-1658.9. Roberts RM, Liu L, Guo Q, Leaman D and Bixby J (1998) The evolution of type Iinterferons. J Interferon Cytokine Res 18:805-816.10. Liu L, Leaman DW and Roberts RM (1998). Possible role of the transcription factor Oct-3/4in control of human chorionic gonadotropin expression. In: D. Carson, ed., EmbryoImplantation: Molecular, Cellular and Clinical Aspects (Serono Symposium), pp.261-270.11. Mannick JB, Hausladen A, Liu L, Hess DT, Zeng M, Miao QX, Kane LS, Gow AJ, StamlerJS (1999). Fas-induced caspase denitrosylation. Science 284:651-654.12. Liu L, Stamler JS. (1999) NO: an inhibitor of cell death. Cell Death Differ 6:937-94213. Liu L, Zeng M, Stamler JS. (1999) Hemoglobin induction in mouse macrophages. Proc NatlAcad Sci USA 96:6643-6647.14. Eu JP, Liu L, Zeng M and Stamler JS (2000). An apoptotic model for nitrosative stress.Biochemistry 39:1040-1047.15. Liu L, Zeng M, Hausladen A, Heitman J, Stamler JS (2000). Protection from nitrosativestress by yeast flavohemoglobin. Proc Natl Acad Sci USA 97:4672-4676.16. Ealy AD*, Larson SF*, Liu L*, Winkelman GL, Kubisch HM, Alexnko AP, Bixby JA,Roberts RM. (2001) Polymorphic forms of expressed bovine interferon-tau genes: relativetranscript abundance during early placental development, promoter sequences of genes andbiological activity of protein products. Endocrinology 142:2906-2915. *These authorscontributed equally.17. Liu L, Hausladen A, Zeng M, Loretta Que, Heitman J, Stamler JS (2001). A metabolicenzyme for S-nitrosothiol conserved from bacteria to humans. Nature 410:490-494.18. Matsumoto A, Comatas KE, Liu L, Stamler JS (2003). Screening for nitricoxide-dependent protein-protein interactions. Science 301:657-661.19. Jesus-Berrios MD, Liu L, Nussbaum JC, Cox GM, Stamler JS, Heitman J (2003).Enzymes that counteract nitrosative stress promote fungal virulence. Current Biology13:1963-1968.146

20. Liu L, Yan Y, Zeng M, Zhang J, Hanes MA, Ahearn G, McMahon TJ, Dickfeld T,Marshall HE, Que LG, Stamler JS (2004). Essential roles of S-nitrosothiols in vascularhomeostasis and endotoxic shock. Cell 116:617-628.21. Que LG, Liu L, Yan Y, Whitehead GS, Gavett SH, Schwartz DA, Stamler JS (2005).Protection from experimental asthma by an endogenous bronchodilator. Science308:1618-1621.22. Bang IS, Liu L, Vazquez-Torres A, Crouch ML, Stamler JS, Fang FC (2006).Maintenance of nitric oxide and redox homeostasis by the Salmonella flavohemoglobinHmp. J Biol Chem 38:28039-28047.23. Foster MW*, Liu L*, Zeng M, Hess DT, Stamler JS (2009). A Genetic Analysis ofNitrosative Stress. Biochemistry 48:792–799. *Co-first author.24. Choudhry S, Que LG, Yang Z, Liu L, Eng C, Kim SO, Kumar G, Thyne S, Chapela R,Meade K, Watson HG, LeNoir M, Rodriguez-Santana JR, Rodriguez-Cintron W, Avila PC,Stamler JS, Burchard EG (2010). GSNO Reductase and β2 Adrenergic Receptor Gene-geneInteraction: Bronchodilator Responsiveness to Albuterol. Pharmacogenetics and Genomics20:351-8.25. Wei W, Li B, Hanes MA, Kakar S, Chen X, Liu L (2010). Deficiency ofS-Nitrosoglutathione Reductase Impairs DNA Repair and Promotes Hepatocarcinogenesis.Science Translational Medicine 2: 19ra13 (PMC3085984).(This paper has been selected and rated by Faculty of 1000 as “Must Read”.)26. Yang Z, Wang Z, Doulias P, Wei W, Ischiropoulos H, Locksley RM, Liu L (2010).Lymphocyte development requires S-nitrosoglutathione reductase. J Immunol, 185:6664-6669(PMC3070165).27. Wei W, Yang Z, Tang CH, Liu L (2011). Targeted deletion of GSNOR in hepatocytes ofmice causes nitrosative inactivation of O 6 -alkylguanine-DNA alkyltransferase and increasedsensitivity to genotoxic diethylnitrosamine. Carcinogenesis 32:973–977 (PMC3128557).28. Lagoda G, Xie Y, Sezen SF, Hurt KJ, Liu L, Musicki B, Burnett AL (2011). FK506Neuroprotection after Cavernous Nerve Injury is Mediated by Thioredoxin and GlutathioneRedox Systems. J Sexual Medicine 8:3325-3334.29. Na B, Huang ZM, Wang Q, Qi ZX, Tian YJ, Lu CC, Yu JW, Hanes MA, Sanjay Kakara S,Huanga EJ, Ou JHJ, Liu L ‡, *, and Yen TSB ‡,† (2011). Transgenic Expression of EntireHepatitis B Virus in Mice Induces Hepatocarcinogenesis Independent of Chronic LiverInjury. PLoS One 6:e26240 (PMC3192172).‡ co-senior author; *Corresponding author; † Deceased August 31, 2009.30. Khan O, Headley M, Gerard A, Wei W, Liu L, Krummel MF (2011). Regulation of T cellpriming by lymphoid-stromal inducible nitric oxidesynthase. PLoS ONE 6:e26138(PMC3215700).31. Tang CH, Wei W, Liu L (2012). Regulation of DNA Repair by S-Nitrosylation. BiochimBiophys Acta 1820:730–735 (PMC3170507; http://dx.doi.org/10.1016/j.bbagen.2011.04.014).32. Ozawa K*, Tsumoto H, Wei W, Tang CH, Komatsubara AT, Kawafune H, Shimizu K, LiuL*, Tsujimoto G (2012). Proteomic analysis of the role of S-nitrosoglutathione reductase inlipopolysaccharide-challenged mice. Proteomics 12, 2024-2035. *Corresponding author.33. Leung J, Wei W, Liu L (2013). S-nitrosoglutathione reductase deficiency increasesmutagenesis from alkylation in mouse liver. Carcinogenesis (in press).147

34. Tang CH, Wei W, Hanes MA, Liu L (2013). Hepatocarcinogenesis driven by GSNORdeficiency is prevented by iNOS inhibition. Cancer Research (in press).Research SupportOngoing Research Support1 R01 CA122359-01A2 NIH/NCI Liu (PI) 05/01/09-4/30/14Title: Role of S-nitroso-glutathione Reductase in Hepatocellular CarcinomaThe goal of this study is to determine whether GSNOR protects DNA repair proteins andplays a role in liver cancer.Role: PICompleted1. Innovative Research Award Liu (PI) 1/1/06-6/30/08Sandler Center for Basic Research in Asthma, UCSFTitle: Role of GSNOR in Asthma (PI)2. Pilot-feasibility funding Liu (PI) 6/1/06-5/31/07UCSF Liver CenterTitle: Potential Role of S-nitroso-glutathione Reductase in Liver Tumorigenesis (PI)3. Research Award Liu (PI) 7/1/2007-6/30/2008Cancer Research Coordinating Committee, UCTitle: Role of S-nitroso-glutathione reductase in protection against carcinogenicN-nitrosamines (PI)4. Research Contract, N30 Pharmaceuticals Liu (PI) 07/01/09-09/30/10Title: Haplosufficiency of S-nitroso-glutathione ReductaseThe goal of this study is to test if GSNOR is haplosufficient for protection against nitrosativestress.Role: PI5 R01 CA055578-14S1 NIH/NCI Pulliam & Liu (PI) 09/30/2009-09/29/2011Title: Role of PreS2 Mutants in Pathogenesis of Chronic Hepatitis BThe goal of this study is to test if GSNOR deficiency functions synergistically with PreS2Mutants in the pathogenesis of chronic hepatitis BRole: one PI of the double-PI team.6. 5P01CA123328 J. Ou (PI) 01/01/2010-05/31/2012Project 2 Title: Hepatic Carcinogenesis Induced By Hepatitis B Virus PreS2 MutantThis project (part of a program project based at the University of Southern California )examines how the preS2 mutant may interact with other HBV proteins and immunological148

factors in causing HCC and the role of the various mutant products of the preS2 mutant incarcinogenesisRole: PI of Project 2.149

BIOGRAPHICAL SKETCHNAMERichard M. Locksley, M.D.eRA COMMONS USER NAMELocksleyPOSITION TITLESandler Distinguished Professor, Departmentof Medicine, University of California, SanFranciscoEDUCATION/TRAININGINSTITUTION AND LOCATION DEGREE YEAR(s) FIELD OF STUDYHarvard College, Cambridge, MA B.A. 1970 BiochemistryUniversity of Rochester, Rochester, NY M.D. 1976 MedicineUniversity of California, San Francisco, CA 1976-80Resident, ChiefResidentUniversity of Washington, Seattle, WA 1980-83Infectious DiseasesFellowPositions and Honors1986-2003 Chief, Division of Infectious Diseases, UCSF Medical Center, SanFrancisco, CA1988-93 Member and Chair (1991-93), Tropical Medicine and ParasitologyStudy Section, NIH1991-94 Co-Director, Immunology Section, Biology of Parasitism Course,Woods Hole, MA1994-99 Chair, Parasitology Pathogenesis Committee, WHO, Geneva1995-05 Council, Chair (1998), Midwinter Conference of Immunologists,Asilomar1995-01 Faculty, Association of American Immunology Annual Course,Advanced Immunology1997- Investigator, Howard Hughes Medical Institute, UCSF1998-01 Member, Chair (2000-01), US-Japan Immunology Board, NIH2002-05 Council, NIAID, National Institutes of Health2003- Director, Strategic Asthma Basic Research Center, UCSFEditorial Boards(1999-03) Immunity, J Clin Invest, Immunology & Cell Biology, Annu RevImmunol150

Honors1991 American Society for Clinical Investigation1994 Association of American Physicians1992-97 Burroughs Wellcome Fund Scholar in Molecular Parasitology1994 Bailey K Ashford Medal, American Society Tropical Medicine andHygiene2001-05 Ellison Medical Foundation Senior Scholar in Global InfectiousDiseases2005 American Academy of Arts & SciencesSelected peer-reviewed publications (in chronological order)1. Grunig G, M Warnock, AE Wakil, R Venkayya, F Brombacher, DM Rennick, DSheppard, M Mohrs, DD Donaldson, RM Locksley, DB Corry. 1998. Requirement forIL-13 independently of IL-4 in experimental asthma. Science 282:2261-63.2. Loots GG, RM Locksley, CM Blankespoor, Z-E Wang, W Miller, EM Rubin, KAFrazer. 2000. Identification of a coordinate regulator of interleukins 4, 13 and 5 bycross-species sequence comparisons. Science 288:136-40.3. Grogan JL, M Mohrs, B Harmon, DA Lacy, JW Sedat, RM Locksley. 2001. Earlytranscription and silencing of cytokine genes underlie polarization of T helper cellsubsets. Immunity 14:205-15.4. Mohrs M, CM Blankespoor, ZE Wang, GG Loots, V Afzal, H Hadeiba, K Shinkai, EMRubin, RM Locksley. Deletion of a coordinate regulator of type 2 cytokine expression inmice. Nature Immunol 2:842-7, 2001.5. Mohrs M, K Shinkai, K Mohrs, RM Locksley. Analysis of type 2 immunity in vivo witha biscistronic IL-4 reporter. Immunity 15:303-11, 2001.6. Shinkai K, M Mohrs, RM Locksley. 2002. Helper T cells regulate type 2 immunity invivo. Nature 420:825-9.7. Voehringer D, K Shinkai, RM Locksley. 2004. Type 2 immunity reflects orchestratedrecruitment of cells committed to IL-4 production. Immunity 20:267-77.8. Mohrs K, AE Wakil, N Killeen, RM Locksley, M Mohrs. 2005. A two-step process forcytokine production revealed by IL-4 dual-reporter mice. Immunity 23:419-29.PMC28263209. Scheu S, DB Stetson, RL Reinhardt, JH Leber, M Mohrs, RM Locksley. 2006.Activation of the integrated stress response during T helper cell differentiation. NatureImmunol 7:644-51. PMC262926910. Voehringer D, TA Reese, X Huang, K Shinkai, RM Locksley. 2006. Type 2 immunityis controlled by IL-4/IL-13 expression in hematopoietic non-eosinophil cells of the innateimmune system. J Exp Med 203:1435-46. PMC211830211. Reese TA, H-E Liang, AM Tager, AD Luster, N van Rooijen, D Voehringer, RMLocksley. 2007. Chitin induces accumulation in tissue of innate immune cellsassociated with allergy. Nature 447:92-6. PMC2527589151

12. Reinhardt RL, H-E Liang, RM Locksley. 2009. Cytokine-secreting follicular T cellsshape the antibody repertoire. Nature Immunol 10:385-93. PMC271405313. Price AE, H-E Liang, BM Sullivan, RL Reinhardt, CJ Eisley, DJ Erle, Grunig G, MWarnock, AE Wakil, R Venkayya, F Brombacher, DM Rennick, D Sheppard, M Mohrs,DD Donaldson, RM Locksley, DB Corry. 1998. Requirement for IL-13 independentlyof IL-4 in experimental asthma. Science 282:2261-63.14. Voehringer D, K Shinkai, RM Locksley. 2004. Type 2 immunity reflects orchestratedrecruitment of cells committed to IL-4 production. Immunity 20:267-77.15. Mohrs K, AE Wakil, N Killeen, RM Locksley, M Mohrs. 2005. A two-step process forcytokine production revealed by IL-4 dual-reporter mice. Immunity 23:419-29.MC282632016. Price AE, H-E Liang, BM Sullivan, RL Reinhardt, CJ Eisley, DJ Erle, RM Locksley.2010. Systemically dispersed innate IL-13-producing cells in type 2 immunity. ProcNatl Acad Sci USA 107:11489-94. PMC2895098.17. Ricardo-Gonzalez RR, A Red Eagle, JI Odegaard, H Jouihan, CR Morel, JE Heredia, LMukudan, D Wu, RM Locksley, A Chawla. 2010. IL-4/Stat6 immune axis regulatesperipheral nutrient metabolism and Insulin sensitivity. Proc Natl Acad Sci USA107:22617-22. PMC301250018. Locksley RM. 2010. Asthma and allergic inflammation. Cell 140:777-83.PMC313438819. Wu D, AB Molofsky, H-E Liang, RR Ricardo-Gonzalez, HA Jouihan, JK Bando, AChawla, RM Locksley. 2011. Eosinophils sustain adipose alternatively activatedmacrophages associated with glucose homeostasis. Science 332:243-7. PMC314416020. Sullivan BM, H-E Liang, JK Bando, D Wu, LE Cheng, JK McKerrow, CDC Allen, RMLocksley. 2011. Genetic analysis of basophil function in vivo. Nat Immunol 12:527-35.PMC3271435Additional Publications (selected from >150 total)1. Amiri P, RM Locksley, TG Parslow, MD Sadick, E Rector, D Ritter, JH McKerrow.1992. Tumor necrosis factor a restores granulomas and induces parasite egg-laying inschistosome-infected SCID mice. Nature 356:604-607.2. Locksley RM, SL Reiner, F Hatam, DR Littman, N Killeen. 1993. Helper T cellswithout CD4: control of leishmaniasis in CD4-deficient mice. Science 261:1448-1451.3. Reiner SL, ZE Wang, F Hatam, P Scott, RM Locksley. 1993. Th1 and Th2 cell antigenreceptors in experimental leishmaniasis. Science 259:1457-60.4. Mougneau E, F Altare, AE Wakil, S Zheng, T Coppola, ZE Wang, R Waldmann, RMLocksley, N Glaichenhaus. 1995. Expression cloning of a protective Leishmaniaantigen. Science 268:563-566.5. Fowell DJ, J Magram, CW Turck, N Killeen, RM Locksley. 1997. Impaired Th2development in the absence of CD4. Immunity 6:559-69.6. Bix M, Locksley RM. 1998. Independent and epigenetic regulation of the interleukin 4alleles in CD4+ T cells. Science 281:1352-4.152

7. Bix M., ZE Wang, B Thiel, NJ Schork, RM Locksley. 1998. Genetic regulation ofcommitment to IL-4 production by a CD4 T cell-intrinsic mechanism. J Exp Med188:2289-99.8. Grunig G, M Warnock, AE Wakil, R Venkayya, F Brombacher, DM Rennick, DSheppard, M Mohrs, DD Symula DJ, KA Frazer, Y Ueda, P Denefle, ME Stevens, Z-EWang, RM Locksley, EM Rubin. 1999. Functional screening of an asthma QTL inYAC transgenic mice. Nature Genetics 23:241-44.9. Stetson DB, M Mohrs, V Mallet-Designe, L Teyton, RM Locksley. 2002. Rapidexpansion and IL-4 expression by Leishmania-specific naive helper T cells in vivo.Immunity 17:191-200.10. Fowell DJ, K Shinkai, XC Liao, AM Beebe, RL Coffman, DR Littman, RM Locksley.1999. Impaired NFATc translocation and failure of Th2 development in itk-deficientCD4 T cells. Immunity 11:399-409.11. Voehringer D, DB Rosen, LL Lanier, RM Locksley. 2004. CD200R family membersrepresent novel DAP12-associated activating receptors on basophils and mast cells. JBiol Chem 279:54117-23.12. Kang S-J, H-E Liang, B Reizis, RM Locksley. 2008. Regulation of hierarchicalclustering and activation of innate immune cells by dendritic cells. Immunity 29:819-33.NIHMS8042213. Voehringer D, D Wu, H-E Liang, RM Locksley. 2009. Efficient generation oflong-distance conditional alleles using recombineering and a dual selection strategy inreplicate plates. BMC Biotechnol 9:69. PMCID: PMC2724507. 2010.14. Price AE, Liang, H-E, Sullivan BM, Reinhardt, RL, Eisley CJ, Erle, DJ, Locksley RM.2010. Systemically dispersed innate IL-13-producing cells in type 2 immunity. Proc NatlAcad Sci USA 107(25):11489-94. PMC2895098.15. Van Dyken SJ, D Garcia, P Porter, X Huang, PJ Quinlan, PD Blanc, DB Corry, RMLocksley. 2011. Fungal chitin from asthma-associated home environments induceseosinophilic lung infiltration. J Immunol 187:2261-2267. PMC315972516. Nguyen KD, Y Qui, X Cui, YP Sharon Goh, J Mwangi, T David, L Mukundan, FBrombacher, RM Locksley, A Chawla. 2011. Alternatively activated macrophagesproduce catecholamines to sustain adaptive thermogenesis. Nature 480:104-108.PMC337176117. Liang H-E, RL Reinhardt, JK Bando, BM Sullivan, I-C Ho, RM Locksley. 2011.Divergent expression patterns of IL-4 and IL-13 define unique functions in allergicimmunity. Nat Immunol 13:58-66. PMC324293818. Gordon E, S Sidhu, Z-E Wang, P Woodruff, S Yuan, M Solon, S Conway, X Huang, RMLocksley, J Fahy. 2012. A protective role for periostin and TGF-b in IgE-mediatedallergy and airway hyperresponsiveness. Clin Exp Allergy 42:144-155. PMC327179219. Thornton EE, MR Looney, O Bose, D Sen, D Sheppard, RM Locksley, X Huang, MFKrummel. 2012. Spatiotemporally separated antigen uptake by alveolar dendritic cellsand airway presentation to T cells in the lung. J Exp Med 209:1183-1199. PMC337173020. Price AE, RL Reinhardt, H-E Liang, RM Locksley. 2012. Marking and quantifyingIL-17A-producing cells in vivo. PLoS ONE 7:e39750. PMC3387253153

21. Dickgreber N, KJ Farrand, N van Panhuys, DA Knight, ML Chong, SMiranda-Hernandez, AG Baxter, RM Locksley, G Le Gros, IF Hermans. 2012.Immature murine NKT cells pass through a stage of developmentally programmed innateIL-4 secretion. J Leukoc Biol (in press)22. Cheng LE, K Hartmann, A Roers, MF Krummel, RM Locksley. 2013. Perivascularmast cells dynamically probe cutaneous blood vessels to capture IgE. Immunity38:166-175. PMC in process23. Oghumu S, R Dong, S Varikuti, T Shawler, T Kampfrath, CA Terrazas, CLezama-Davila, BMM Ahmer, CC Whitacre, S Rajagopalan, R Locksley, AH Sharpe,AR Sataskar. 2013. Distinct populations of innate CD8 T cells revealed in a CXCR3reporter mouse. J Immunol (in press).24. Molofsky AB, JC Nussbaum H-E Liang, SJ Van Dyken, LE Cheng, A Mohapatra, AChawla, RM Locksley. 2013. Innate lymphoid type 2 cells ILC2) sustain visceraladipose tissue eosinophils and alternatively activated macrophages. J Exp Med (inpress). PMC in process25. Van Dyken SJ, RM Locksley. 2013. Interleukin-4- and interleukin-13-mediatedalternatively activated macrophages: roles in homeostasis and disease. Annu RevImmunol 31:317-43. PMC in process26. Spits H, D Artis, M Colonna, A Diefenbach, JP Di Santo, G Eberl, S Koyasu, RMLocksley, ANJ McKenzie, RE Mebius, F Powrie, E Vivier. 2013. Innate lymphoid cells– a proposal for a uniform nomenclature. Nature Rev Immunol 13:145-149. PMC inprocess27. Heredia JE, L mukundan, FM Chen, AA Mueller, R Deo, RM Locksley, TA Radno, AChawla. 2013. Type 2 innate signals regulate functionality of fibro/adipogenicprogenitors to facilitate muscle regeneration. Cell (in press).Research SupportActiveNot assigned Locksley (PI) 10/97-9/12 (budgeted annually)Howard Hughes Medical InstituteActivation of ImmunityThe major goals of this project are to provide new strategies to optimize host defense andvaccines and to treat pathologic immune responses associated with autoimmunity and allergy.Support from HHMI pays Dr. Locksley's salary.R37 AI26918 Locksley (PI) 7/88-3/16NIH/NIAIDParasite immunity orchestrated by Th2 cellsThe major goal of this project is to identify the role of basophils and eosinophils required forimmunity to parasitic helminths.154

RO1 AI30663 Locksley (PI) 6/08-5/13NIH/NIAIDInitiation of allergic immunity by parasitesThe major goals of this grant are to understand the mechanism by which chitin in helminthescontributes to eosinophilic inflammation in tissues in response to migrating organisms and eggs.U19 AI077439 Sheppard (PI) 3/08-2/13NIH/NIAIDMechanisms of initiation and persistence of allergic asthmaThe major goals of this grant are to understand mechanisms of allergic lung inflammationinduced by fungi in murine models and human studies.Role: PI Subproject 1P01 AI078869 DeFranco (PI) 7/08-6/13NIH/NIAIDCross-talk between innate and adaptive immune cells in inflammation and autoimmunityThe major goals are to assess the role of innate signaling pathways in the induction of mucosalresponses to pathogens.Role: PI Subproject 4P01 AI119944 Fahy (PI) 7/12-6/12NIH/NHLBIInnate and Adaptive Immune Responses in TH2-High AsthmaProject 1: Innate Helper Type-2 Cells in Allergic LungThe goal of this project is to focus on the role of iH2 cells as proximal regulators of TH2inflammation in the airway. This project proposes to characterize markers for these cells,delineate their role in allergic airway responses and collaborate with investigators in Project 3 toadvance understanding of iH2 cells in human asthma.Larry L. Hillblom Center for the immunobiology of type 2 diabetes(Chawla PI, Locksley co-PI) 1/09-12/12The goal of this project is to understand the inferface between immune cell activation andmetabolic disorders.Completed5-2008-214 Locksley (PI) 12/07-12/08Juvenile Diabetes Research Foundation Innovative GrantsFunctional immune cell activation in type 1 diabetesThe major goal of this project was to use mice with marker alleles in informative cytokine genesto identify evidence for functionally important cytokine elaboration in mediating peripheralinsulin sensitivity.155

BIOGRAPHICAL SKETCHNAMEWilliam E. Seaman, M.D.eRA COMMONS USER NAMEBSEAMANPOSITION TITLEProfessor of Medicine and of Microbiology andImmunology, UCSFEDUCATION/TRAININGINSTITUTION AND LOCATION DEGREE YEAR(s) FIELD OF STUDYPrinceton University, Princeton, NJ A.B. 1964 EnglishHarvard Medical School, Boston, MA M.D. 1969 MedicineMassachusetts General Hospital, Boston, MA Resident 1969-1971 Internal MedicineArthritis and Rheumatism Branch, NIAMDD,NIH Bethesda, MDFellow 1971-1974Immunology andRheumatologyMassachusetts General Hospital, Boston, MAChiefResident1974-1975 MedicineMassachusetts General Hospital, Boston, MA Fellow 1976 RheumatologyPositions and HonorsAcademic Positions1976 - 1984 Assistant Professor of Medicine, University of California San Francisco1978 - Present Staff Physician, San Francisco VA Medical Center1981 - 1992 Chief, Arthritis/Immunology Section, San Francisco VA Medical Center1984 - 1988 Associate Professor of Medicine, University of California, San Francisco1988 - Present Professor of Medicine and of Microbiology and Immunology,University of California San Francisco1992 - 1999 Chief, Medical Service, San Francisco VA Medical Center1999 - Present Chief, Immunology Section, San Francisco VA Medical CenterOther Recent Positions1999 - Present Research Director, American Asthma Foundation1999 - 2003 NIH Study Section, Experimental Immunology2000 - 2008 Director, Macrophage Biology Laboratory, Alliance for Cellular Signaling2002 - 2005 President, Society for Natural Immunity2011 – Present Associate Chair of Medicine for Research, UCSF156

Honors1964 AB cum laude1969 MD cum laude2007 Master, American College of RheumatologyMedical and Research Society Memberships and Board Certifications1973 to Present American College of Rheumatology1974 American Board of Internal Medicine1978 American Board of Rheumatology1979 to Present American Federation for Clinical Research1980 to Present American Association of Immunologist1984 to Present American Society for Clinical Investigation1994 to Present American Association of Physicians1998 to Present Society for Natural Immunity2001 to Present American Association for Cancer Research2007 to Present International Bioiron Society2007 to Present International Society of NeuroimmunologyEditorships1985-1989 Associate Editor, Journal of Immunology1989-1993 Section Editor, Journal of Immunology1992-1997 Consulting Editor, Journal of Clinical Investigation2005 to Present Faculty of 100015 Selected Peer-Reviewed Publications (of 93)1. Wofsy D, Seaman WE: Successful treatment of autoimmunity in NZB/NZW mice withmonoclonal antibody to L3T4. J Exp Med 161:378-391, 1985.2. Seaman WE, Eriksson E, Dobrow R, Imboden JB: Inositol trisphosphate is generated by arat natural killer cell tumor in response to target cells or to cross-linked monoclonalantibody OX-34: possible signaling role for the OX-34 determinant during activation bytarget cells. Proc Natl Acad Sci USA 84:4239-4243, 1987.3. Seaman WE, Niemi EC, Stark MR, Goldfien RD, Pollock AS, Imboden JB: Molecularcloning of gp42, a cell-surface molecule that is selectively induced on rat natural killer cellsby interleukin-2: Glycolipid membrane anchoring and capacity for transmembranesignaling, J Exp Med. 173:251-260, 1991.4. Yokoyama WM, Ryan JC, Hunter JJ, Smith HMC, Stark M, Seaman WE. cDNA cloningof mouse NKR-P1 and genetic linkage with Ly-49: Identification of a natural killer genecomplex on mouse chromosome VI. J Immunol 147:3229, 1991.157

5. Ryan JC, Turck J, Niemi EC, Yokoyama WM, Seaman WE. Molecular cloning of theNK1.1 antigen, a member of the NKR-P1 family of natural killer cell activation molecules.J Immunol. 149:1631-1635, 1992.6. Ryan JC, Niemi EC, Nakamura MC, Seaman WE. NKR-P1A is a target-specific receptorthat activates natural killer cell cytotoxicity. J Exp Med 181:1911-1915, 1995.7. Nakamura, MC, Linnemeyer, PA, Niemi EC, Mason L, Ortaldo JR, Ryan JC, Seaman WE.Mouse Ly-49D recognizes H-2Dd and activates natural killer cell cytotoxicity. J Exp Med,189:493-500, 1999.8. Nakamura MC, Hayashi S, Niemi EC, Ryan JC, Seaman, WE. Activating Ly-49D andinhibitory Ly-49A NK cell receptors demonstrate distinct requirements for interaction withH2-Dd. J Exp Med 7:192:447-54, 2000.9. Daws MR, Sullam PM, Niemi EC, Chen TT, Seaman WE. Pattern recognition byTREM-2: binding of anionic ligands. J Immunol. 171:594-9, 2003.10. Chen TT, Li L, Chung D-H, Allen CDC, Torti SV, Torti FM, Cyster JG, Chen C, Brodsky,FM, Niemi EC, Nakamura MC, Seaman WE, Daws MR. TIM-2 is expressed on B cellsand in liver and kidney and it is a receptor for H ferritin endocytosis. J Exp Med.202:955-65, 2005.11. Roach TI, Rebres RA, Fraser ID, Decamp DL, Lin KM, Sternweis PC, Simon MI, SeamanWE. Signaling and cross-talk by C5a and UDP in macrophages selectively use PLCbeta3 toregulate intracellular free calcium. J Biol Chem 283(25):17351-61, 2008.12. N'Diaye EN, Branda CS, Branda SS, Nevarez L, Colonna M, Lowell C, Hamerman JA,Seaman WE. TREM-2 (triggering receptor expressed on myeloid cells 2) is a phagocyticreceptor for bacteria. J Cell Biol 184(2):215-23, 2009.13. Hsieh CL, Koike M, Spusta SC, Niemi E, Yenari M, Nakamura MC, and Seaman WE. Arole for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia. JNeurochem 109(4):1144-1156, 2009.14. Li L, Fang CJ, Ryan JC, Niemi EC, Lebrón JA, Björkman PJ, Arase H, Torti FM, Torti SV,Nakamura MC, Seaman WE. Binding and uptake of H-ferritin is mediated by humantransferrin receptor-1. Proc Natl Acad Sci USA. Proc Natl Acad Sci USA 107(8):3505-10,2010.15. Rebres, RA, Roach TIA, Fraser IDC, Philip F, Moon C, Lin KM, Liu J, Santat L, Cheadle L,Ross EM, Simon MI, Seaman WE. Synergistic Ca 2+ responses by Ga i - and Gaq-coupledG-protein-coupled receptors require a single PLCb isoform that is sensitive to both Gbg andGaq. J Biol Chem 286:1-10, 2011Research SupportOngoing Research SupportTitle: The Role of Microglial Subsets in Regulating Brain InjuryAgency/Type: Department of Defense PT075679 PI: WE Seaman 7/1/06 to 6/30/2012Role: Principal InvestigatorProgram: These studies examine the role of microglial subsets in the response to TBI. Theyexamine the hypothesis that microglia, like macrophages may be divided into pro-inflammatory158

vs. reparative subsets, and that injury following TBI may be improved by driving microglia fromthe former to the latter. Key persons are Christine Hsieh, a postdoctoral fellow, my colleague,Mary Nakamura, MD, and Jialing Liu, PhD, a colleague in Neurosurgery who is expert in TBI.Ongoing Mentored GrantTitle: The role of CCR2 and Macrophages in Traumatic Brain InjuryAgency/Type: Department of Veterans Affairs PI: Christine Hsieh 1/1/2011 to 12/31/2013Role: MentorProgram: This is a VA Career Development Award to Christine Hsieh, PhD, a postdoctoralfellow in my laboratory for whom I am the mentor on this award. Dr. Hsieh has been studyingtraumatic brain injury as part of my DoD grant (above). As part of this work, she showed thatTBI results in an influx of macrophage to the brain, and that this influx is primarily dependent onthe chemokine receptor, CCR2. This grant has allowed her to study the functional consequencesof this response and to develop as an independent investigator. Key persons in addition to Dr.Hsieh and myself include our colleague, Mary Nakamura.Completed support (last 3 years)Title: Role of the Tim-2 Receptor in Immunity and AutoimmunityAgency/Type: NIH RO1 AI061164-01A1 Seaman (PI) 7/1/05 to 3/31/11Role: Principal InvestigatorProgram: These studies examined the role in immunity and autoimmunity of TIM-2, a receptorexpressed on mouse lymphocytes and on liver cells and renal tubule cells159

BIOGRAPHICAL SKETCHNAMEDean Sheppard, M.D.eRA COMMONS USER NAMEsheppardPOSITION TITLEProfessor of MedicineEDUCATION/TRAININGINSTITUTION AND LOCATION DEGREE YEAR(s) FIELD OF STUDYHarvard College, Cambridge, MA AB 6/72SUNY at Stony Brook, Stony Brook, NY MD 6/75 MedicineUniversity of Washington, Seattle, WA Resident 7/75-6/78 Internal MedicineUniversity of California, San Francisco, San Fellow 7/78-6/81 PulmonaryFranciscoPositions2009-Present Chief, Pulmonary, Critical Care, Allergy and Sleep Division, UCSF1986-Present Director, Lung Biology Center, University of California, San Francisco1999-2004 Acting Director, Sandler Basic Asthma Research Center, UCSF1981-1987 Assistant Professor of Medicine, University of California, San Francisco1987-1992 Associate Professor of Medicine, University of California, San Francisco1992-Present Professor of Medicine, University of California, San Francisco1997-2009 Associate Chair for Biomedical Research, Department of Medicine, UCSFOther ExperienceMember, NHLBI Program Project Review Committee, 1998-2002, Chair 2000-2002Member, Lung Injury and Repair Study Section, 2004-2008, Chair 2006-2008Scientific Advisory Board, Parker B. Francis Foundation 2006-2009Editorial Board, Journal of Clinical Investigation 2003-presentEditorial Board, Clinical and Translational Science 2008-presentAssociate Editor, American Journal of Respiratory Cell and Molecular Biology 1995-2002Editorial Board, American Journal of Physiology; Lung Cell and Molecular Biology 1996-2007Chair, Oversight Committee, NHLBI Lung Tissue Consortium, 2004-presentHonors and AwardsElected Member, American Society for Clinical Investigation, 1992Elected Member, Association of American Physicians, 1995160

Clean Air Award, American Lung Association of California, 1995Parker B. Francis Lecturer, Aspen Lung Conference, 1996Lifetime Scientific Achievement Award, American Thoracic Society, 1998Jerome I. Flance Visiting Professor, Washington University, 2000Roger Mitchell Lecturer, Aspen Lung Conference, 2001NIH Merit Award, 2004-2014Robert Johnston Lecturer, Drexel University, 2005McClement Lecturer, New York University, 2006Kass Medal, University of Nebraska, 2007Amberson Lecturer, American Thoracic Society, 2010Selected Relevant Publications (from a total 252)1. Grunig G, Warnock M, Wakil AE, Venkayya R, Brombacher F, Rennick DM, SheppardD, Mohrs M, Donaldson DD, Locksley RM, Corry DB. Requirement for IL-13independently of IL-4 in experimental asthma. Science 1998; 282:2261-3.PMID:98569502. Munger JS, Huang XZ , Kawakatsu H , Griffiths MJD, Dalton SL, Wu JF, Pittet JF,Kaminiski N, Garat C, Matthay MA, Rifkin DB, Sheppard D. The integrin avb6 bindsand activates latent TGFb1: a mechanism for regulating pulmonary inflammation andfibrosis. Cell 1999; 96:319-328.PMID:100253983. Kaminski N, Allard J, Pittet J-F, Zuo F, Griffiths MJD, Morris D, Huang XZ, SheppardD, Heller RA. Global analysis of gene expression in pulmonary fibrosis reveals distinctprograms regulating lung inflammation and remodeling. Proc Nat Acad Sci 2000;97:1778-1783.PMID:106775344. Pittet J-F, Griffiths MJD, Geiser T, Kaminski N, Dalton SL, Huang X Brown LAS,Gotwals PJ, Koetiansky VE, Matthay MA, Sheppard D. TGFβ is a critical mediator ofacute lung injury. J. Clin Invest 2001; 107:1529-1536.5. Morris DG, Huang X, Kaminski N, Wang Y, Shapiro SD, Dolganov G, Glick, A,Sheppard D. Loss of integrin avb6-mediated TGFb activation causes Mmp12-dependentemphysema. Nature 2003 422:169-173. PMID: 126347876. Chen C, Young BA, Coleman CS, Pegg AE, Sheppard D. Spermidine/SpermineN 1 -Acetyltransferase specifically binds to the integrin α9 subunit cytoplasmic domainand enhances cell migration J Cell Biol 2004 167:161-170. PMID: 154797427. Vlahakis NE, Young BA, Atakilit A, Hawkridge AE, Issaka RB, Boudreau N, SheppardD. Integrin alpha 9beta 1 directly binds to vascular endothelial growth factor (VEGF)-Aand contributes to VEGF-A induced angiogenesis. J Biol Chem. 2007 282:15187-15196.PMID: 173633778. Jenkins RG, SuX, Su G, Scotton CJ, Camerer E, Laurent GJ, Davis JE, Chambers RC,Matthay MA, Sheppard D. Ligation of the protease-activated receptor-1 induces αvβ6integrin-dependent TGFβ activation and promotes acute lung injury. J. Clin Invest 2006116:1606-1614.9. Travis MA, Reizis B, Melton AC Masteller E, Tang Q, Proctor J, Wang Y, Bernstein X,Huang X, Riechardt L, Bluestone J, Sheppard D. Loss of integrin αvβ8 on dendritic161

cells causes autoimmunity and colitis in mice. Nature 2007 449:361-365.PMID:1769404710. Su G, Hodnett M, Wu N, Atakilit A, Kosinski C, Godzich M, Huang XZ, Kim K, FrankJA, Matthay MA, Sheppard D*, Pittet J-F*. Integrin avb5 regulates lung vascularpermeability and pulmonary endothelial barrier function Am J Respir Cell Mol Biol 200736:377-86 (*denotes equal contributions) PMID:1707977911. Ganter MT, Roux J, Miyazawa B, Howard M, Frank JA, Su G, Sheppard D, VioletteSM, Weinreb PH, Horan GS, Matthay MA, Pittet JF. Interleukin-1β causes acute lunginjury via αvβ5 and αvβ6 integrin-dependent mechanism Circ Res 2008 102:804-12.12. Atabai K, Jame S, Kuo A, Lam M, Dehart G, Xia DD, Azhar N, Werb Z, Sheppard D.Mfge8-mediated collagen endocytosis limits the severity of fibrotic disease J Clin Invest2009 219:3713-22. PMCID: PMC278680413. Melton A, Bailey-Bucktrout SL, Travis MA, Fife BT, Bluestone JA, Sheppard D. avb8integrin on dendritic cells regulates Th17 cell development and experimental autoimmuneencephalomyelitis in mice. J Clin Invest 2010. 120:4436-44. PMCID: PMC299359514. Hogmalm A, Sheppard D, Lappalainen U, Bry K. Beta6 integrin subunit deficiencyalleviates lung injury in a mouse model of bronchopulmonary dysplasia. Am J Respir CellMol Biol 2010 43:88-98. PMCID: PMC291157315. Spassov DS, Wong CH, Sergina N, Ahuja D, Fried M, Sheppard D, Moasser MM. Asrc-driven phosphotyrosine signaling switch determines the anchorage state of epithelialcells. Mol Cell Biol 2011. 31:776-82. PMCID: PMC302865316. Su G, Atakilit A, Li T. J, Wu N, Bhattacharya M, Zhu J, Li E, Sun S, Chen R, Su C,Sheppard D. Integrin αvβ3 prevents vascular leak in mice by regulating cortical actinformation in endothelial cells. Am J Resp Crit Care Med 2012 (in press)17. Kudo M, Melton AC, Chen C, Engler M, Huang KE, Ren X, Wang Y, Bernstein X, Li J,Atabai K, Huang X, Sheppard D. IL-17A produced by ab T cells drives airway smoothmuscle contraction. Nature Medicine 2012 (in press).18. Giacomini M, Travis M, Sheppard D. Epithelial cells utilize cortical actin/myosin toactivate latent TGF-β through integrin αvβ6-dependent physical force. Exp Cell Res 2012318:716-22. PMID: 22309779.19. Sugimoto K, Kudo M, Sundaram A, Ren X, Huang K, Bernstein X, Wang Y, RaymondWW, Erle D, Abrink M, Caughey GH, Huang X, Sheppard D. The avb6 integrinmodulates airway hyperresponsiveness by regulating intra-epithelial mast cells. J ClinInvest 2012 (in press).20. Chen C, Kudo M, Rutaganira F, Takano H, Lee C, Atakilit A, Robinett, KS, Uede T,Wolters P, Shokat KM, Huang X, Sheppard D. Integrin alpha9beta1 in airway smoothmuscle regulates a novel brake on exaggerated murine and human airway narrowing JClin Invest 2012 122:2916-27 PMID 22772469.21. Bhattacharya M, Su G, Su X, Oses-Prieto JA, Li JT, Huang X, Hernandez H, Atakilit A,Burlingame AL, Matthay M, Sheppard D. IQGAP1 is necessary for pulmonary vascularbarrier protection in murine acute lung injury and pneumonia Am J Physiol: Lung Celland Mol Biol 2012 303:L12-19 PMID: 22561460.162

Research SupportOngoingR01 HL102292 (Sheppard) 12/03/10-11/30/14NIHIntegrin-mediated Regulation of Airway Smooth MuscleThe major goals of this project are to determine the mechanisms by which the alpha9beta1integrin inhibits the sensitivity of airway smooth muscle to contraction induced by agonists of Gprotein coupled receptors.R37 HL53949 (Sheppard)4/1/04-3/31/14 (merit award)NIHIn Vivo Functions of Pulmonary IntegrinsThe major goals of this project are to determine the roles of TGFβ1 activation in the induction oflung inflammation and protection from pulmonary fibrosis in integrin β6 subunit null mice.U19 AI077439 (Sheppard) 3/1/08-2/28/13NIH/NIAID-Project 1 and Core AMechanisms of Initiation and Pesistence of Allergic AsthmaThe major goals of this project are to determine the roles of integrin-mediated TGFβactivation in regulating auto-immunity, regulatory T cells and airway hyperresponsivenessafter chronic allergen challenge in mice.Scleroderma Research Foundation (Sheppard) 5/1/12-4/30/13Role of αv integrins in SclerodermaThe goals of this project are to determine whether specific integrins expressed on epithelialcells or myofibroblasts could be effective therapeutic targets for treatment of SclerodermaP01 HL108794 (Sheppard) 07/01/2012–6/30/17NIH/NHLBI- Project 2 and Core ATargeting Epithelial Cells to Treat Pulmonary FibrosisOverall project goal: This grant will address two critical needs - developing effective treatmentsfor pulmonary fibrosis and better ways to determine if drugs are actually hitting their targets. Bytargeting specific well-defined pathways, modifying drugs for delivery into the airways, andidentifying markers of drug efficacy from readily available sites, we hope to dramaticallyimprove current approaches to treatment of pulmonary fibrosis.T32 HL007185 (Sheppard) 07/01/2012–6/30/17NIH/NHLBIMultidisciplinary training program in lung diseaseRole: Program Co-PI163

Overall project goal: This is a training grant to train future leaders in basic, clinical andtranslational pulmonary scienceRecently completedR01 HL083950 (Sheppard) 4/1/06-3/31/11NIH/NHLBIRegulations of Pulmonary Vascular Permeability by Integrin AlphaVbeta5The major goals of this project were: 1) To identify the pathways by which αvβ5 facilitatedRhoA activation and contributed to pulmonary vascular permeability. 2) To determine howthe integrin β5 subunit contributed to the formation of multi-protein signaling complexesthat regulated endothelial permeability. 3) To determine whether the pathways examined inaims 1 and 2 were broadly important in in vivo models of non-cardiogenic pulmonaryedema.U19 AI077439-02S1 (Sheppard) 8/15/09-7/31/11NIH/NIAID (Administrative Supplement Award)Mechanisms of Initiation and Persistence of Allergic AsthmaThis administrative supplement to our U19 grant had three goals – to develop an assay formeasurement of environmental chitin, to replace our outdated tissue processor and processour backlog of fixed murine and human tissues, and to develop multi-plexed, bead basedassays for measurements of multiple secreted proteins in small volume samples from humanand murine airways.R01 AI024674 (Sheppard) 3/1/06-2/28/10NIH/NIAIDNovel Leukocyte IntegrinsThe major goal of this project was to understand how glycan phosphoatidly inositolanchored proteins influenced the function of Fc and complement receptors on macrophagesand dendritic cells.(Sheppard) 6/8/09-12/31/11University of Edinburgh (Subcontract)The Role of the Alphavbeta8 Integrin in Hepatic Inflammation and FibrosisThe subcontract is to support a postdoctoral fellow, Neil Henderson, to work in Dr.Sheppard’s laboratory. Dr. Henderson was working on the mechanisms of activation ofTGF beta in the liver.The major goals of this project are to determine the mechanisms by which the alpha9beta1integrin inhibits the sensitivity of airway smooth muscle to contraction induced by agonists of Gprotein coupled receptors.164

BIOGRAPHICAL SKETCHNAMEJeoung-Sook Shin, Ph.D.eRA COMMONS USER NAMESHINJSPOSITION TITLEAssistant ProfessorEDUCATION/TRAININGINSTITUTION AND LOCATION DEGREE YEAR(s) FIELD OF STUDYSeoul National University, Seoul, Korea BS 1988-1993 ChemistrySeoul National University, Seoul, Korea MS 1993-1995 BiochemistryDuke University, Durham, NC Ph.D. 1997-2002 PathologyDuke University, Durham, NC Postdoc 2002-2003 PathologyYale University, New Haven, CT Postdoc 2003-2008 Cell BiologyProfessional Positions1996 Research Associate, Cheong-Am Biotech, Seoul, Korea2008 Assistant Professor, University of California San Francisco, Dept. ofMicrobiology Immunology & Sandler Asthma Basic Research CenterHonors and Awards1999 The Best Research Student Award in the Department of Pathology9 th Graduate Student Symposium, Duke University2004 The Jane Coffin Childs Memorial Fund Research Fellowship Award2009 Strategic Innovative Award in Asthma Research2009 Cancer Research Institute Investigator AwardProfessional Memberships2008 - 2009 American Thoracic Society, member2010 American Society of Cell Biology, member2011 - Present American Association of Immunologists, member165

4. Locksley, R.M., Reiner, S.J., Sadick, M.D., Wang, Z., Heinzel, H.P. andHoladay, B.J.: Evidence for restricted V-D-Jß T cell receptor usage in the Th2response to Leishmania major. 1991 FASEB J. 5:A1369.5. Reiner SL, S Zheng, Z Wang, L Stowring, RM Locksley. 1994. Leishmaniapromastigotes evade IL-12 induction by macrophages and stimulate a broad range ofcytokines from CD4 cells during initiation of infection. J Exp Med 179:447-56.6. Loh, E., Wang, M., Wang, Z., Hyjek, E., and Kozbor, D.: Expression functionalg/d T cell receptor recognize tetanus toxin. J of Cellular Biochemistry. 1992 165(D):67.7. Kozbor, D., Hyjek, E., Wiaderkiewicz, R., Wang, Z., Wang, M. and Loh, E.:Competitor mRNA fragments for quantitation of cytokine specific transcripts in celllysates. Molecular Immunology, 1993. 30(1):1.8. Reiner SL, Z Wang, F Hatam, P Scott, RM Locksley. 1993. Th1 and Th2 cellantigen receptors in experimental leishmaniasis. Science 259:1457-60.9. Wang Z, SL Reiner, F Hatam, FP Heinzel, J Bouvier, CW Turck, RMLocksley. 1993. Targeted activation of CD8 cells and infection ofb2-microglobulin-deficient mice fail to confirm a primary protective role forCD8 cells in experimental leishmaniasis . J Immunol 151:2077-86.10. Reiner SL, S Zheng, Z Wang, L Stowring, RM Locksley. 1994. Leishmaniapromastigotes evade IL-12 induction by macrophages and stimulate a broad range ofcytokines from CD4 cells during initiation of infection. J Exp Med 179:447-56.11. Wang ZE, SL Reiner, S Zheng, D Dalton, RM Locksley. 1994. CD4+ effector cellsdefault to the Th2 pathway in IFN-g-deficient mice. J Exp Med 179:1367-71.12. Wang, Z., Zheng S., Corry D.B., Dalton, D.K., Seder, R.A., Reiner, S.L., andLocksley, R.M.: Interferon-g-dependent effects of interleukin-12 administered duringacute or established infection due to Leishmania major. Proc. Natl. Acad. Sci. USA.1994 91(24):12932-6.13. Mougneau E, F Altare, AE Wakil, S Zheng, T Coppola, ZE Wang, R Waldmann,RM Locksley, N Glaichenhaus, N. 1995. Expression cloning of a protectiveLeishmania antigen. Science 268:563-6.14. Wakil AE, ZE Wang, RM Locksley. 1996. Leishmania major: targeting IL-4 insuccessful immunomodulation of murine infection. Exp Parasitol 84:214-22.15. Pingel S, ZE Wang, RM Locksley. 1998. Distribution of protein kinase C isoformsafter infection of macrophages with Leishmania major. Infect Immun 66:1795-9.16. Wakil AE, ZE Wang, JC Ryan, DJ Fowell, RM Locksley. 1998. Interferon gammaderived from CD4(+) T cells is sufficient to mediate helper cell type 1 development.J Exp Med 188:1651-6.17. Bix, M, ZE Wang, B Thiel, NJ Schork, RM Locksley. 1998. Genetic regulation ofcommitment to interleukin 4 production by a CD4(+) T cell-intrinsic mechanism. JExp Med 188:2289-99.18. Symula DJ, KA Frazer, Y Ueda, P Denefle, ME Stevens, ZE Wang, RM Locksley,EM Rubin. 1999. Functional screening of an asthma QTL in YAC transgenic mice.Nat Genet 23:241-4.169

19. Cretu G, RM Locksley, ZE Wang, EM Rubin, KA Frazer. 2000. Functional analysisof CNS-1 in YAC transgenic mice. Science 288:136-9.20. Lacy DA, ZE Wang, DJ Symola, C McArthur, EM Rubin, KA Frazer, RM Locksley.2000. Faithful expression of the human 5q31 cytokine cluster in transgenic mice. JImmunol 164:4569-75.21. Loots GG, RM Locksley, CM Blankespoor, ZE Wang, W Miller, EM Rubin, KAFrazer. 2000. Identification of a coordinate regulator of interleukins 4, 13, and 5 bycross-species sequence comparisons. Science 288:136-140.22. Mohrs M, CM Blankespoor, Z Wang, GG Loots, V Afzal, H Hadeiba, K Shinkai,EM Rubin, RM Locksley. 2001. Deletion of a coordinate regulator of type 2cytokine expression in mice. Nat Immunol 2, 842-7.23. Grogan JL, ZE Wang, S Stanley, B Harmon, GG Loots, EM Rubin, RM Locksley.2003. Basal chromatin modification at the IL-4 gene in helper T cells. J Immunol171:6672-9.24. Xu M, ZE Wang, RM Locksley. 2004. Innate immune responses in peptidoglycanrecognition protein L-deficient mice. Mol Cell Biol 24:7949-57.25. Reinhardt RL, S Hong, SJ Kang, ZE Wang, RM Locksley. 2006. Visualization ofIL-12/23p40 in vivo reveals immunostimulatory dendritic cell migrants that promoteTh1 differentiation. J Immunol 177:1618-27.26. Cheng LE, ZE Wang, RM Locksley. 2010. Murine B cells regulate serum IgElevels in a CD23-dependent manner. J Immunol 185:5040-7.27. Yang Z, ZE Wang, PT Doulias, W Wei, H Ischiropoulos, RM Locksley, L Liu.2010. Lymphocyte development requires S-nitrosoglutathione reductase. J Immunol185:6664-9.28. Gordon E, S Sidhu, Z-E Wang, P Woodruff, S Yuan, M Solonm S Conway, XHuang, RM Locksley, J Fahy. 2012. A protective role for periostin and TGF-β inIgE-mediated allergy and airway hyperresponsiveness. Clin Exp Allergy 42: 144-155.PMC3271792170

BIOGRAPHICAL SKETCHNAMEArthur Weiss, M.D., Ph.D.eRA COMMONS USER NAMEweissaPOSITION TITLEProfessor of Medicine and of Microbiology andImmunologyEDUCATION/TRAININGINSTITUTION AND LOCATION DEGREE YEAR(s) FIELD OF STUDYUniversity of Chicago Ph.D. 1978 ImmunologyUniversity of Chicago M.D. 1979 MedicinePositions and Employment1979-1980 Postdoctoral Fellow, Swiss Institute for Experimental Cancer Research,Lausanne, Switzerland1980-1982 Resident, Department of Medicine, University of California, San Francisco(UCSF)1982-1984 Fellow in Rheumatology/Clinical Immunology, UCSF1982-1985 Associate, Howard Hughes Medical Institute, UCSF1984-1985 Instructor, Department of Medicine, Division of Rheumatology/ClinicalImmunology, UCSF1985-1989 Assistant Investigator, Howard Hughes Medical Institute, UCSF1985-1989 Assistant Professor of Medicine, Microbiology and Immunology, UCSF1987- Chief, Division of Rheumatology/Clinical Immunology, Department of Medicine,University of California, San Francisco1989-1993 Associate Professor or Medicine, Microbiology and Immunology, UCSF1989-1994 Associate Investigator, Howard Hughes Medical Institute, UCSF1991- Ephraim P. Engleman Distinguished Professor of Rheumatology, UCSF1992- Professor of Medicine, Microbiology and Immunology, UCSF1993- Investigator, Howard Hughes Medical Institute, UCSF1998-2005 Associate Director, The Rosalind Russell Medical Research Center for Arthritis,UCSF2002-2006 Director, Medical Scientist Training Program (MSTP), UCSF2007-2010 Co-Director, Institute for Molecular Medicine, UCSF171

Other Experience and Professional Memberships1986-1991 Councilor, American Federation for Clinical Research1991 President, Western Region of the American College of Rheumatology1998-2002 Member, Allergy and Immunology Study Section (NIH)1999- Chair, Scientific Advisory Board, American Asthma Foundation2000-2002 Chair, Allergy and Immunology Study Section (NIH)2003-2010 Council, American Association of Immunologists2008-2009 President, American Association of Immunologists2005- Advisory Council, RIKEN Research Center for Allergy & ImmunologyYokohama, JapanHonors1990 Young Investigator Award, Western Society for Clinical Investigation1990 Henry Kunkel Young Investigator Award, American College of Rheumatology1993 Junior Investigator Award, American Association of Immunologists1997 Lee C. Howley Prize, Arthritis Foundation1998 Forty-First Faculty Research Lecturer, University of California, San Francisco2001 American Association of Immunologist-Huang Foundation Meritorious Career Award2003 Fellow, American Academy of Arts and Sciences2004 Member, National Academy of Sciences2004 Fellow, American Academy of Microbiology2004 Member, Institute of Medicine2004 Distinguished Investigator Award, American College of Rheumatology2004 Walter Bauer Visiting Professor in Rheumatology, Massachusetts GeneralHospital2004 Bridget Ogilvie Lecture, University of Dundee, Scotland2004 Sue Kim Hansen Lecture, Boston University School of Medicine2005 Dan H. Campbell Memorial Lecture, Midwinter Conference of Immunologists,Asilomar, CA2005 Visiting Professor, Harvard Medical School Rheumatology Division2005 Beirne B. Carter Lecture in Immunology, University of Virginia2005 Dan H. Campbell Memorial Lecture, Midwinter Conference of Immunologists,Asilomar, CA2006 Keynote Speaker, American Association of Immunologists, AdvancedImmunology Course2009 Ishizaka Lecture, La Jolla Institute for Allergy and Immunology2009 46 th Charles A. Stuart Memorial Lecture, Brown University2010 Dorothy Baugh Harmon Endowed Lectureship, Oklahoma MedicalResearch Foundation2012 Lifetime Achievement Award, American Association of Immunologists2012 UCSF Lifetime Achievement in Mentoring Award172

Selected Peer-reviewed Publications (from a total of 207)1. Deindl S, Kadlecek TA, Brdicka T, Cao X, Weiss A, and Kuriyan. Structuralbasis for the inhibition of the tyrosine kinase activity of ZAP-70. Cell, 129:735-746, 2007. PMID: 175124072. Palacios E, Weiss A. Distinct roles for Syk and ZAP-70 during thymicdevelopment. J Exp Med. 2007; 204: 1703-15. PMID: 17606633. PMVIF:PMV2118636.3. Zhu JW, Brdicka T, Katsumoto TR, Lin J, and Weiss A. Structurally distinctphosphatases CD45 and CD148 both regulate B cell and macrophageimmunoreceptor signaling. Immunity. 28:183-196. 2008. PMC22651064. Hsu L-Y, Tan YX, Xiao Z, Malissen M, and Weiss A. A hypomorphic allele ofZAP-70 reveals a distinct thymic threshold for autoimmune disease versusautoimmune reactivity. J. Exp. Med., 206:2527-2541, 2009. PMC27688605. Das J, Ho M, Zikherman J, Govern C, Yang M, Weiss A, Chakraborty AK, RooseJP. Digital signaling and hysteresis characterize Ras activation in lymphoid cells.Cell. 2009; 136337-51. PMCID: PMC2662698.6. Zikherman J, Hermiston M, Steiner D, Hasegawa K, Chan A and Weiss A.PTPN22 deficiency cooperates with the CD45 E613R allele to break tolerance ona non-autoimmune background. J. Immunol., 182:4093-4106. 2009.PMC27659787. Deindl S, Kadlecek TA, Cao X, Kuriyan J, and Weiss A. Stability of anautoinhibitory interface in the structure of the tyrosine kinase ZAP-70 impacts Tcell receptor response. Proc. Natl. Acad. Sci. USA 106:20699-20704, 2009.PMC27785808. Zikherman J, Jenne C, Watson S, Doan K, Raschke W, Goodnow CC, and WeissA. The balance between positive and negative regulatory roles of CD45 during TCR signaling varies throughout T cell development. Immunity, 32:342-354.2010. PMC28651989. Phee H, Dzhagalov I, Mollenauer M, Wang Y, Irvine DJ, Robey ., and Weiss A.Regulation of thymocyte positive selection and motility by GIT2. Nat. Immunol.,11:503-511. 2010. PMID: 2043162110. Au-Yeung BB, Levin SE, Zhang C, Hsu, L-Y, Cheng DA, Killeen N, Shokat Kand Weiss A. A genetically selective inhibitor demonstrates a function for thekinase Zap70 in regulatory T cells independent of its catalytic activity. Nat.Immunol., 11:1085-1093. 2010. PMID: 21037511. Limnander A, Depeille P, Freedman TS, Liou J, Leitges M, Kurosaki T, RooseJP, and Weiss A. Stim1, PKCd, and RasGRP proteins set a threshold for proapoptoticErk signaling during B cell development. Nat. Immunol., 12:425-433.2011. PMID: 2144193412. Zhu JW, Doan K., Park J, Chau AH, Zhang H, Lowell CA, and Weiss A. Distinctfunctions of receptor-like tyrosine phosphatases CD45 and CD148 inchemoattractant-mediated neutrophil migration and response to S. aureusinfection. Immunity. 35:757-769. 2011. PMID: 22078799173

13. Zikherman J, Doan K, Parameswaran R, Raschke W, and Weiss A. Quantitativedifferences in CD45 expression unmask functions for CD45 in B-celldevelopment, tolerance and survival. Proc. Natl. Acad. Sci. USA. ePub ahead ofprint. 2011. PMID: 2213546514. Wei P, Wong WW, Corcoran EE, Peisajovich SG, Weiss A, and Lim WA.Bacterial virulence proteins as tools to synthetically rewire kinase pathways inyeast and immune cells. Nature. 488:384-388. 2012. PMCID: PMC342241315. Zikherman, J., Parameswaran, R., and Weiss. A. Endogenous antigen tunesresponsiveness of antigen recepor signaling in B cells but not T cells. Nature.489:160-164. 2012. PMID: 2290250316. Mukherjee S, Zhu J, Zikherman J, Parameswaran R, Kadlecek TA, Wang Q, Au-Yeung B, Ploegh H, Kuriyan J, Das J*, and Weiss, A* Monovalent andmultivalent ligation of the B cell receptor exhibit differential dependence uponSyk and Src family kinases. Sci. Signal. 2013. Jan 1;6(256):ra1 PMID:23281368 *co-corresponding authors17. Zikherman J, Parameswaran R, Hermiston M, and Weiss A. The wedge domainof the receptor-like tyrosine phosphatase CD45 enforces B cell tolerance byregulating substrate specificity. J. Immunol., in press. 2013.Research SupportOngoing Research SupportHoward Hughes Medical Institute Weiss (PI) 07/01/85-08/31/12Cell surface molecules and molecular events involved in human T cell activationThe goal is to study cell surface molecules and molecular events involved in T cellactivation. HHMI personnel (3 postdocs and 4 technicians) focus on structure of theTCR and the ZAP-70 protein tyrosine kinase.Role: Principal Investigator1 RC2 AR058947-01 (A.Weiss) 09/25/09-08/31/12 NoCost ExtensionNIH/NIAMSAn allosteric inhibitor of ZAP-70 as a novel therapeutic for autoimmune diseaseThe goals of this project are develop and allosteric inhibitor of ZAP-70 and determinethe preclinical utility of a model catalytic inhibitor of ZAP-70 in preclinical models ofdisease.Role: Principal Investigator1PO1 AI091580-0107/15/11-06/30/16NIH/NIAID (Program Leader A. Weiss)Deconstructing and Reconstructing the T Cell Signaling NetworkThe goals of this project are to understand the molecular mechanims that operate atthe plasma membrane to control the specificity, activity and regulation of the TCRsignaling mechanisms that lead to protein tyrosine phosphorylation and Ras activity.174

A119632Weiss (PI)07/01/12-06/30/14American College of RheumatologyIdentifying antigen-specific T cells in mouse and human arthritisThe goals of this grant are to understand how antigen specific T cells are stimulatedand to identify and characterize the T cell antigen receptors in mouse and humanarthritis.Role: Principal InvestigatorCompleted ResearchRO1 AI066120 Weiss (PI)02/15/06-01/31/12 No CostExtensionNIH/NIAIDFunction of the RPTP CD148 in the Hematopoietic LineageThe goals in this research 1) characterize the developmental, functional, andbiochemical consequences of CD148 loss on the T cell lineage, with emphasis onTCR signaling pathways; 2) characterize the developmental, functional andbiochemical consequences of the loss CD148 on the B cell lineage, with emphasis onthe antigen receptor signaling pathways; and, 3) characterize the biochemical,functional and immunological consequences of inactivating the CD148 gene inmyeloid cells on integrin and Fc-receptor dependent pathways.Role: Principal InvestigatorPO1 AI35297 Abbas (PI) 08/01/06-07/31/11NIH/NIAIDPeripheral Tolerance and AutoimmunityProject #3Regulation of CD45 signaling in tolerance and autoimmunityThe goals of this project are to exploit a newly discovered model of autoimmunitycaused by a genetic disruption that prevents CD45 dimerization as a model for defectsin signaling receptors that interfere with self-tolerance. T cell lineages responsiblefor autoimmunity and the role of antigen will be defined, and the molecular basis ofCD45 regulation of lymphocyte responses and self-tolerance will be examined.Role: Co-InvestigatorPN2 EY016546 Lim (PI) 09/01/08-08/30/09NIHCellular Control: Synthetic Signaling/Motility (RMI)The goals of this project are to engineer cells or cell-like molecular assemblies thatperform “smart” therapeutic functions: tasks such as tissue repair or “search anddeliver” actions to treat microscopic tumors or cardiovascular lesions.Role: Project Principal Investigator175

RO1 AI52127 Goodnow (PI) 09/15/02-06/30/07NIH/NIAIDGenes for Tolerance and Immunity ConsortiumA consortium of investigators will develop and validate screening tests to identifymice with altered immune regulation, and then define the mutant gene, molecularpathways, and cellular processes revealed by each new mouse strain.Role: Co-Investigator176

BIOGRAPHICAL SKETCHNAMEJonathan S. Weissman, Ph.D.eRA COMMONS USER NAMEWEISSMANPOSITION TITLEProfessor, University of California San FranciscoInvestigator, Howard Hughes Medical InstituteEDUCATION/TRAININGINSTITUTION AND LOCATION DEGREE YEAR(s) FIELD OF STUDYHarvard University A.B. 1984-1988 PhysicsMassachusetts Institute of Technology Ph.D. 1988-1993 PhysicsPositions and Honors1993 - 1996 Postdoctoral Fellow, Yale University, Structural and Biochemical Studies ofGroEL1996 - 2000 Assistant Professor, University of California San Francisco, Departments ofCellular & Molecular Pharmacology, and Biochemistry & Biophysics2000 - 2005 Assistant Investigator, Howard Hughes Medical Institute2000 - 2003 Associate Professor, University of California San Francisco, Departments ofCellular & Molecular Pharmacology, and Biochemistry & Biophysics2003 - Present Professor, University of California San Francisco, Departments of Cellular &Molecular Pharmacology, and Biochemistry & Biophysics2005 - Present Investigator, Howard Hughes Medical InstituteOther Experience and Professional Memberships1999 Keynote Speaker at Scripps Research Institute Society of Fellows AnnualSymposium2001 to Present Associate Editor, Molecular Cell2001 - 2003 Ad hoc reviewer, CDF-2 NIH study section2002 Organizer, Second International Yeast Prion Symposium2002 to Present Organizer, Cold Spring Harbor Heat Shock Meeting2003 to Present Editorial Board, BMC Cell Biology2003 Burroughs Wellcome Visiting Scholar, University of Chicago2003 to Present Editorial Board, Public Library of Science (PLoS) Biology2004 Organizer, FASEB meeting on Amyloid and Diseases of Misfolding20052004 - 2008Co-organizer, The Protein Society 19 th Annual MeetingPermanent Member, NIH Molecular Biology & Protein Processing StudySection2005 - 2008 Editorial Board, Molecular Biology of the Cell2005 External Reviewer, Lawrence Berkeley National Lab Physical BiosciencesDivision177

2005 - 2007 Advisory Board NIH on Amyloid Diseases2005 Organizer, Mini-symposium of Quality Control for the Annual AmericanSociety of Cell Biology (ASCB) Meeting2006 to Present Member, Yeast Genetics & Molecular Biology Meeting Program Committee2006 to Present Editorial Board, Journal of Molecular Biology2007 to Present Board of Reviewing Editors, Science2007 to Present Scientific Advisory Board, GlycoFi (Merck & Company, Inc.)2008 to Present Scientific Advisor, Merck Research Labs2008 to Present Editorial Board, Cell2009 Program Committee Member, ASCB2009 to Present Editorial Board, Current Opinion in Cell Biology2009 Keynote address at the annual retreat of the Genentech ResearchOrganization2009 Keynote lecture at the annual International Conference on Systems Biology2009 to Present Scientific Advisory Board, Proteostasis Therapeutics2009 Member, NAKFI Steering Committee on Synthetic Biology2010 Member, NIH College of CSR ReviewersHonors and Awards1987 Phi Beta Kappa, Harvard University1988 Summa cum laude in Physics, Harvard University1988 Karl Taylor Compton Pre-doctoral Fellowship1988 National Science Foundation Pre-doctoral Fellowship1996 David and Lucile Packard Fellowship1997 Searle Scholars Program Fellowship2000 Assistant Investigator, Howard Hughes Medical Institute2004 Protein Society’s Irving Sigal Young Investigator’s Award2008 Raymond & Beverly Sackler International Prize in Biophysics2009 Alexander M. Cruikshank Lecturer, Gordon Research Conference on Stress2009 Elected to the National Academy of Sciences2010 David Perlman Award Lecturer of the ACS Division of Biochemical Technology(BIOT)2010 Fellow, American Academy of MicrobiologySelected Peer-reviewed Publications (In chronological order; 13 selected of 119 publications)1. Breslow DK, Cameron DM, Collins SR, Schuldiner M, Stewart-Ornstein J, NewmanHW, Braun S, Madhani HD, Krogan NJ, Weissman JS. (2008) A comprehensivestrategy enabling high-resolution functional analysis of the yeast genome. NatMethods, 5:711-8. PMC27560932. Breslow DK, Collins SR, Bodenmiller B, Aebersold R, Simons K, Shevchenko A,Ejsing CS, Weissman JS. (2010) ORM family proteins mediate sphingolipidhomeostasis. Nature, 463:1048-53. PMC2877384178

3. Ingolia NT, Ghaemmaghami S, Newman JRS, Weissman JS. (2009) Genome-wideanalysis in vivo of translation with nucleotide resolution using ribosome profiling.Science, 324(5924)218-23. PMC27464834. Breslow DK, Weissman JS. (2010) Membranes in Balance: Mechanisms ofSphinogolipid Homeostasis. Mol Cell, 40(2): 267-79. PMC29876445. Churchman LS, Weissman JS. (2011) Nascent transcript sequencing visualizestranscription at nucleotide resolution. Nature, 469: 368-73. PMID 212488446. Ingolia NT, Lareau LF, Weissman JS. (2011) Ribosome profiling of mouseembryonic stem cells reveals the complexity and dynamics of Mammalian proteomes.Cell, 147: 789-802. PMC32252887. Oh E, Becker AH, Sandikci A, Huber D, Chaba R, Gloge F, Nichols RJ, Typas A,Gross CA, Kramer G, Weissman JS, Bukau B. (2011) Selective ribosome profilingreveals the co-translational chaperone action of trigger factor in vivo. Cell, 147:1295-1308. PMC32778508. Brar GA, Yassour M, Friedman N, Regev A, Ingolia NT, Weissman JS. (2012)High-resolution view of the yeast meiotic program revealed by ribosome profiling.Science, 335: 552-7. PMID 221944139. Li GW, Oh E, Weissman JS. (2012) The anti-Shine-Dalgamo sequence drivestranslational pausing and codon choice in bacteria. Nature, 484: 538-41.PMC333887510. Ingolia NT, Brar GA, Rouskin S, McGeachy AM, Weissman JS. (2012) Theribosome profiling strategy for monitoring translation in vivo by deep sequencing ofribosome-protected mRNA fragments. Nature Protocols, 7: 1534-50. PMID2283613511. Carvunis AR, Rolland T, Wapinski I, Calderwood MA, Yildirim MA, Simonis N,Charloteaux B, Hidalgo CA, Barbette J, Santhanam B, Brar GA, Weissman JS,Regev A, Thierry-Mieg N, Cusick ME, Vidal M. (2012) Proto-genes and de novogene birth. Nature, 487: 370-4. PMC340136212. Brandman O, Stewart-Ornstein J, Wong D, Larson A, Williams CC, Li GW, Zhou S,King D, Shen PS, Weibezahn J, Dunn JG, Rouskin S, Inada T, Frost A, WeissmanJS. (2012) A ribosome-bound quality control complex triggers degradation of nascentpeptides and signals translation stress. Cell, 151: 1042-54. PMID 2317812313. Stern-Ginossar N, Weisburd B, Michalski A, Le VT, Hein MY, Huang SX, Ma M,Shen B, Qian SB, Hengel H, Mann M, Ingolia NT, Weissman JS. (2012) Decodinghuman cytomegalovirus. Science, 338: 1088-93. PMID 23180859Research SupportOngoing Research SupportNo Project Number (Weissman) 10/01/2000-8/31/2017Howard Hughes Medical InstitutePrion-Based Inheritance, Protein Folding, and Analysis of Cellular Systems179

This grant supports our studies of how cells insure that proteins fold into their correct shape, aswell as the role of protein misfolding in disease and normal physiology. We are also developingexperimental and analytical approaches for exploring the organizational principles of biologicalsystems.Hughes Collaborative Investigator Award -- No Project Number (Weissman) 09/18/2012 -08/17/2017Howard Hughes Medical InstituteA combined chemical and genetic approach to explore how chaperone and stress networksmaintain the integrity of oncogene-addicted cancer cellsP01 AG70770-15 (Prusiner; Weissman Project 2) 04/01/11 - 3/31/16NIHMolecular Pathogenesis of Age-Dependent CNS DegenerationSpecific aims of this project are to 1) identify a novel prion domain in the yeast protein New1p;2) identify novel prion phenomena; and 3) establish a genetic screen in yeast to studypropagation of the mammalian prion protein (PrP).U01 CA168370-01 (McManus) 05/01/12 – 04/30/17NIHBay Area Cancer Target Discovery and Development NetworkThe overarching goal of the BACTDDN is to discover and characterize new cancer targets andtheir modulators, placing them into druggable pathways. Specific aims: 1) develop EXPANDlibraries targeting cancer-specific genetic alterations; 2) identify novel drivers that showtransforming potential in immortalized primary cells; and 3) produce genetic EMAPs to uncoverpathway relationships between candidate drivers.P50 GM073210 (Stroud; Weissman - Key Personnel) 09/01/09 – 08/31/2014NIH/NIGMSCenters for Innovation in Membrane Protein Production for Structure DeterminationThe goals are to develop approaches that will make the solution of simple membrane proteinstructures routinely achievable and develop novel methods that can be applied to morecomplicated membrane proteins containing multiple subunits of the same (homo-oligomers) anddifferent (hetero-oligomers) structure; and to produce and determine structures for complexesthat are formed between membrane proteins and their soluble protein partners, small ligandsand/or macromolecules.U01 GM098254 (Agard/Walter) 09/2012 - 08/2017NIHStructural Basis of Protein HomeostasisTo obtain structural insights into the mechanism by which unfolded and non-native states arerecognized by the cytosolic (Hsp70, TRiC chaperones) and ER (UPR and ERAD pathways)protein homeostasis machineries.180

P50 GM102706-01 (Cate) 09/2012 - 08/2017NIHCenter for RNA Systems BiologyThis Center aims to use systems biological methods to discover the regulation of mRNA fatecontrolled by RNA structural elements in pre-mRNAs and mRNAs.No Project Number (Bivona & Weissman) 02/01/2012 - 1/30/2014California Institute for Quantitative BiosciencesDiscovery of Rational Companion Targets in Human Lung CancerThe goal is to define rational polytherapies for lung cancer patients through genome-wide RNAiscreening. Specific aims of this Rogers Foundation Bridging the Gap Award project are: 1)determine which genes act together to make cancer tumor cells more vulnerable; 2) test drugcombinations against these targets; 3) identify additional drug combinations to tackle othersubtypes of lung cancers, and expand studies to include different categories of cancer.Completed Research SupportSandler Center for Drug Discovery (Weissman) 11/01/11 - 10/31/2012Identifying and Characterizing Asiatic Cholera Host FactorsSpecific aims of this project are: 1) Develop a quantitative functional reporter assay for action ofcholera toxin in cell culture; 2) Conduct a comprehensive genome-wide screen for factorsaffecting cholera toxin action; 3) Validate and characterize the targets in physiological assays forcholera activity.SABRE Center (Weissman) 01/01/09-06/30/11Sandler Asthma Basic REsearch CenterDefining the Function of ORMDL3 and Exploring its Potential Role in AsthmaSpecific aims of this project are: 1) Define the function of ORM genes in yeast; 2) Characterizethe function of the human ORM homolog ORMDL3; 3) Examine the potential role of ORMDL3in asthma.P0032295 (Weissman) 12/01/09 - 11/30/2010AFAR (Glenn Foundation for Medical Research)Monitoring the Effects of Aging on Protein TranslationUsing a ribosome profiling approach pioneered in our lab, we will investigate the impact ofaging and the accumulation of misfolded proteins on protein synthesis in a yeast model system.Sandler Center (Weissman and F 01/15/09-01/14/10Sandler Program in Basic SciencesDefining Roles on N-Glycans in Endopasmic Reticulum-Mediated Quality ControlSpecific aims of this project are: 1) Biochemical characterization of the putative mannosidaseHtm1; and 2) Elucidation of contributions of glycan and misfolded protein components tosubstrate recognition in late stages of ERAD-L pathway.181

Fight for Mike Program (Weissman) 07/23/07-07/22/09California Institute for Quantitative Biosciences (QB3)Identification of Factors Important for the Folding of Mammalian Prion ProteinThe broad goal of our studies is to identify key factors required for folding of the mammalianprion protein.182

BIOGRAPHICAL SKETCHNAMEZena Werb, Ph.D.eRA COMMONS USER NAMEwerbzenaPOSITION TITLEProfessor of AnatomyEDUCATION/TRAININGINSTITUTION AND LOCATION DEGREE YEAR(s) FIELD OF STUDYUniversity of Toronto, Toronto, Canada B.Sc. 06/1966 BiochemistryRockefeller University, New York Ph.D. 06/1971 Cell BiologyStrangeways Research Laboratory, Cambridge, Postdoc. 1971-73 Protein ChemistryPositions1973-1975 Research Scientist, Strangeways Res. Lab., Cambridge, United Kingdom1975-1976 Visiting Assistant Professor of Medicine,Dartmouth Medical School, Hanover, NH1976-1980 Assistant Professor Radiobiology, RadiologyUniversity of California, San Francisco1979-1980 Assistant Professor Anatomy, University of California San Francisco1980-1983 Associate Professor of Anatomy and RadiologyUniversity of California, San Francisco1983-Present Professor Anatomy, UCSF1985-1986 Visiting Professor, Sir William Dunn School of PathologyUniversity of Oxford, United Kingdom1998 Visiting Professor, Institut Curie, Paris1999-Present Vice-chair, Dept. of Anatomy, University of California, San Francisco2006-2008 Visiting Professor, Max-Planck Institute for BiochemistryMartinsried, GermanyOther Experience and Professional MembershipsEditorial Boards1983-1985 Journal of Cell Biology1982-1987 American Journal of Physiology1985-2004 Journal of Experimental Medicine1990-2001 Science1999-Present Matrix Biolog1999-Present Neoplasia2000-2009 Cell2001-Present Developmental Cell2001-Present Cancer Cell183

2002-2006 Molecular Biology of the Cell2007-2009 Genes & Development2009-Present Current Opinion in Cell Biology2010-Present Guest Editor, Proc. National Academy Science, USA2010-Present Member, Editorial Board, Disease Models and MechanismsProfessional Memberships1976-present American Society for Cell Biology1979-present American Society for Biochemistry and Molecular Biology1967-71 & American Association for the Advancement of Science1979-present1988-present Society for Developmental Biology2001-present American Association for Cancer Research2001-present American Society for Matrix Biology2004-present International Society for DifferentiationScientific Leadership1990-1992 Member, Cell and Molecular Biology Panel, National Cancer Institute ofCanada1991-1995 Member, Board of Scientific Counselors, NIAMS1992-1995 Council Member, American Society for Cell Biology1993-1995 Council Delegate, Am. Assoc. for the Advancement of Science1994-2001 Member, Scientific Advisory Board, Keystone Symposia2001-2003 Council Member, American Society for Matrix Biology2001 NIH Oncological SS Boundaries Team2002 NIH Biochem SS, ad hoc2003-2005 Council Member, International Society for Matrix Biology2003-2006 Board of Directors, AACR2005 President, American Society for Cell Biology2007-2009 Nominating Committee, AACR2007 Member, NIH ZRG1 ICI–D012008 Reviewer, NIH Pioneer Awards2008 Chair, NIH ZRG1 MOSS-A (02)2008-2010 Chair, NIH ICI Study Section2009-2012 Chair, American Academy of Arts and Sciences, Membership SelectionCommittee Class II, section2010 Co-organizer, CNIO Cancer Symposium on Frontiers in Invasion andMetastasis, Madrid2011-Present Member, Steering Committee, AACR Council of Scientific Advisors2011-2016 Member, Scientific Advisory Board, Max Planck Institute for Biology ofAgeing, Cologne, GermanyHonors1971-1973 Fellow, Medical Research Council, Canada1982 R.R. Bensley Memorial Award, American Association of Anatomists1985-1986 Fellow, John Simon Guggenheim Foundation1992 Elected Fellow, American Association for the Advancement of Science1996 FASEB Excellence in Science Award184

1998 Rotschild/Mayent Fellowship, Institut Curie2002 Elected Member, Institute of Medicine2003 Elected Fellow, American Academy of Arts and Sciences2003 Doctor of Medicine (honoris causa), University of Copenhagen2006-2007 Alexander von Humboldt Foundation (Germany) Research Award2007 E.B. Wilson Medal, American Society for Cell Biology2009 Colin Thomson Memorial Medal, AICR2010 Elected Member, National Academy of Sciences2010 American Society for Cell Biology, Women in Cell Biology Senior Award2011 Zero Breast Cancer 2011 Community Breast Cancer Research AwardNamed Lectureships (selected)2001 44th Faculty Research Lecture Award, University of California, San Francico2001 H.B. Parker Lecture, Pacific Northwest National Lab.2003 Pharmacology Founders’ Seminar, Wayne State University, Detroit, Michigan2004 Schlessinger Lecturer, BIDMC, Harvard Medical School2004 A. S. Wiener Lecture, NY Blood Center2005 Maud L. Menten Lecture, University of Pittsburgh2005 17th Otto Herz Memorial Lecture, Tel Aviv University, Israel2008 Whitley Lecture, Northwest Developmental Biology Society2009 Suzanne M. Bernier Lecture in Skeletal Biology, University of Western Ontario,London, Canada2011 John H. Blaffer Lecture, M.D. Anderson Cancer Center, University of Texas,Houston TX2011 McAllister Lecture, Pathology Grand Rounds, Yale Medical School, New Haven CT2012 Keynote Lecture, 28 th International Association for Breast Cancer ResearchBreakthrough Breast Cancer Conference, Manchester, UKSelected Publications 15 Selected Publications (>450 total full publications)1. Sternlicht MD, A. Lochter, CJ Sympson, B Huey, JP Rougier, JW Gray, D Pinkel, MJBissell & Z Werb (1999). The stromal proteinase MMP-3/stromelysin-1 promotesmammary carcinogenesis. Cell. 98: 137-146. PMCID: PMC28532552. Coussens LM & Z Werb (2002). Inflammation and cancer. Nature 420:860-867.PMID: 12490959; PMCID: PMC28030353. Egeblad MA, J Ewald, HA Askautrud, BE Welm, M Truitt, E Bainbridge, G Peeters,M Krummell & Z Werb (2008). Visualizing stromal cell dynamics in differenttumor microenvironments by spinning disk confocal microscopy. Dis. Model. Mech.1:155-167. PMCID: PMC2562195.4. Ewald AJ, A Brenot, M Duong, BS Chan & Z Werb (2008). Collective epithelialmigration and cell rearrangements drive mammary branching morphogenesis. Dev.Cell. 14:570-581. PMCID: PMC2773823.5. Kouros-Mehr H, SK Bechis, EM Slorach, LE Littlepage, M Egeblad, AJ Ewald, SYPai, IC Ho & Z Werb (2008). GATA-3 links tumor differentiation and disseminationin a luminal breast cancer model. Cancer Cell. 13:141-152. PMCID: PMC2262951.185

6. Welm BE, GJP Dijkgraaf, AS Bledau, AL Welm & Z Werb (2008). Lentiviraltransduction of stem cells for genetic analysis of mammary development and breastcancer. Cell Stem Cell. 2:90-102. PMCID: PMC2276651.7. Kessenbrock K, V Plaks & Z Werb (2010). Matrix metalloproteinases: Regulators ofthe tumor microenvironment. Cell. 141:52-67. PMCID: PMC286205.8. Littlepage LE, MD Sternlicht, N Rougier, J Phillips, E Gallo, Y Yu, K Williams, ABrenot, JI Gordon & Z Werb (2010). Matrix metalloproteinases contribute distinctroles in neuroendocrine prostate carcinogenesis, metastasis, and angiogenesisprogression. Cancer Res. 70:2224-2234 PMID: 20215503; PMCID: PMC2840052.9. Slorach EM, J Chou & Z Werb (2011). Zeppo1 is a novel metastasis promoter thatrepresses E-cadherin expression and regulates p120-catenin isoform expression andlocalization. Genes Dev. 25: 471-484. [Epub ahead of print February 11, 2011].PMCID: PMC3049288.10. Caudrillier A, K Kessenbrock, BM Gilliss, JX Nguyen, MB Marques, M Monestier, PToy, Z Werb & MR Looney (2012). Platelets induce neutrophil extracellular traps intransfusion-related acute lung injury. J. Clin. Invest. 122(7):2661–2671. [Epub aheadof print, Jun 11]. PMID: 22684106; PMCID: PMC3386815.11. Engelhardt J, B Boldajipour, P Beemiller, P Pandurangi, C Sorenson, Z Werb, MEgeblad & MF Krummel (2012). Marginating dendritic cells of the tumormicroenvironment cross-present antigens and stably engage tumor-specific T cells.Cancer Cell. 21:402-417. PMID: 22439936; PMCID: PMC3311997.12. Littlepage LE, AS Adler, H Kouros-Mehr, G Huang, J Chou, SR Krig, OL Griffith,JE Korkola, K Qu, DA Lawson, Q Xue, MD Sternlicht, GJP Dijkgraaf, P Yaswen,Hope S Rugo, CA Sweeney, CC Collins, JW Gray, HY Chang & Z Werb (2012).The transcription factor ZNF217 is a prognostic biomarker and therapeutic targetduring breast cancer progression. Cancer Discov. 2:638-651 [Epub June 22]. PMID:22728437.13. Nakasone E, HA Askautrud, T Kees, V Plaks, AJ Ewald, MG Rasch, YX Tan, J Qin,M Fein, J Park, P Sinha, MJ Bissell, E Frengen, Z Werb & M Egeblad (2012).Imaging tumor-stroma interactions during chemotherapy reveals microenvironmentalcontributions to chemoresistance. Cancer Cell. 21:488-503. PMCID: PMC3332002.14. Phillips JJ, A Ward, E Huillard, A Robinson, DH Lum, MY Polley, SD Rosen, DHRowitch & Z Werb (2012). Heparan sulfate sulfatase SULF2 regulates PDGFRasignaling and growth in malignant glioblastoma. J. Clin. Invest. 122:911–922 [EpubFeb. 1]. PMID: 22293178; PMCID: PMC3287216.15. Chou J, JH Lin, A Brenot, JW Kim, S Provot & Z Werb (2013). GATA3 suppressesmetastasis and modulates the tumor microenvironment by regulating miR-29expression. Nat. Cell Biol. In press.186

Research SupportOngoingNIH/NCI R01 CA129523-05 Werb (PI) 07/01/08 - 04/30/13Transcriptional Regulation of Breast Cancer MetastasisThis study addresses how GATA-3 regulates the differentiated state of breast tumors.NCI R01 CA057621-20 Werb (PI) 04/15/93 - 05/31/13Role of Metalloproteinases in Mammary Gland RemodelingThis consortium grant between UCSF and LBNL determines functions of ECM-degradingproteinases and inhibitors in mammary epithelium during development.NIH/NIAID P01 AI053194-10 Mostov (PI) 09/30/02 - 08/31/13Mucosal Immune Barrier in Infection and InflammationThis project studies the role of the inflammatory response in mucosal epithelia.Role: Leader, Project 4 and Core CNIEHS/NCI 5U01 ES019458-03 (Werb, PI) 09/01/10-04/30/15Environmental Effect on The Mammary Gland Across The LifespanThe major goal of this program is to determine the susceptible times in breast developments andhow they are affected by environmental stressors.17UB-8705-02 California Breast Cancer Research Program (Werb, PI) 09/01/11-08/31/14Biomarkers for environmental exposures in breast cancerThe major goal of this project is to find glycan biomarkers that are induced by exposure toenvironmental stressors.CompletedNIH/NIAMS R01 AR046238-10 Werb (PI) 09/01/99 - 01/31/11Extracellular Remodeling in Bone Development And RepairThis project studied the role of extracellular remodeling in bone development and repair.NCI P01 CA072006-10 Werb (PI) 07/07/03 – 06/30/10Proteases in Cancer: Biology and Drug DevelopmentThis program tested new animal models of invasive cancer with antiprotease therapy.Role: Project Leader, Project 3 and Core ANIH/NCI U01 CA105379-05 Hanahan (PI) 09/27/04 - 03/31/09Immune Enhancement and Therapy in Cancer/ Mouse Models of Human Cancer ConsortiumThis project addressed the immunobiology of carcinogenesis in genetically engineered mousemodelsRole: Co-INIH/NIEHS U01 ES012801-07 Hiatt (PI), Werb (PI) 09/29/03 - 07/31/11This project studied environmental effects on the molecular architecture and function of themammary gland.Role: PI, Collaborative Project 1187

SU2C-AACR-DT0409-03 Gray, Slamon (Dream team leaders) 10/01/09 - 09/30/12Stand Up to Cancer-American Association for Cancer Research Dream Team TranslationalCancer Research GrantPersonalizing Treatment of Metastatic Breast CancerThe goal of this project was to develop xenograft models of human of drug-resistant, metastaticbreast cancers to then test therapies selected based on the “omic” features of the metastatictumors.Role: Dream Team Member188

BIOGRAPHICAL SKETCHNAMEPrescott Gurney Woodruff, M.D., M.P.H.eRA COMMONS USER NAMEwoodruffpPOSITION TITLEAssociate Professor of Medicine in ResidenceEDUCATION/TRAININGINSTITUTION AND LOCATION DEGREE YEAR(s) FIELD OF STUDYWesleyan University, Middletown, CT B.A. 6/1989 LettersColumbia College of Physicians & Surgeons, NY M.D. 6/1993 MedicineMassachusetts General Hospital Resident 1993-1996 Internal MedicineHarvard School of Public Health M.P.H. 6/1998 EpidemiologyBrigham and Women’s Hospital Fellow 1997-1998 Resp EpidemiologyUniversity of California, San Francisco Fellow 1998-2002 Pulmonary/CriticalCarePositions and Honors1993-1994 Intern in Internal Medicine; Massachusetts General Hospital, Boston, MA1994-1996 Resident in Internal Medicine; Massachusetts General Hospital, Boston, MA1996-1998 Research Fellow, Department of Emergency Medicine; Massachusetts GeneralHospital, Boston, MA1997-1998 Clinical and Research Fellow, Channing Laboratory, Department of MedicineBrigham and Women’s Hospital, Boston, MA1998-2002 Clinical and Research Fellow, Pulmonary/Critical Care Medicine &Cardiovascular Research Institute, Department of Medicine, University ofCalifornia San Francisco, San Francisco, CA2002-2005 Assistant Adjunct Professor; University of California San Francisco2005- 2010 Assistant Professor in Residence, Pulmonary/Critical Care Medicine, Departmentof Medicine and CVRI, University of California San Francisco2010- Associate Professor in Residence, Division of Pulmonary and Critical CareMedicine, Department of Medicine and CVRI, University of CaliforniaSan Francisco2012- Vice Chief for Research, Division of Pulmonary, Critical Care, Sleep and Allergy,University of California, San Francisco189

Other Experience and Professional Memberships2004- Steering Committee, NIH NHLBI COPD Clinical Research Network2009- Steering Committee, NIH NHLBI Spiromics Network2011- Steering Committee, NIH NHLBI Severe Asthma Research ProgramHonors1993 Alpha Omega Alpha, Columbia College of Physicians and Surgeons, NY, NY2012 Elected to membership, American Society of Clinical InvestigationSelected peer-reviewed publications (Selected from 58 peer-reviewed publications)1. Woodruff PG, Boushey HA, Dolganov GM, Barker CS, Yang YH, Donnelly S,Ellwanger A, Sidhu SS, Dao-Pick TP, Pantoja C, Erle DJ, Yamamoto KR, Fahy JV.Genome-Wide Profiling Identifies Epithelial Cell Genes Associated with Asthma andwith Treatment Response to Corticosteroids. Proc Natl Acad Sci U S A. 2007 Oct2;104(40):15858-63. PMCID: PMC20004272. Goswami S, Angkasekwinaim P, Shan M, Greenlee KJ, Barranco WT, PolikepahadS, Seryshev A, Redding D, Singh B, Sur S, Woodruff PG, Dong C, Corry DB,Kheradmand F. Divergent Roles for Airway Epithelial MMP7 and Retinoic Acid inExperimental Asthma, Nature Immunology, 2009 May;10(5):496-503. PMID:19329997 PMC Journal – In Process3. Woodruff PG, Modrek B, Choy DF, Jia G, Abbas AR, Ellwanger A, Koth LL, ArronJR, and Fahy JV. Th2-driven inflammation defines major sub-phenotypes of asthma.Am J Respir Crit Care Med Sep 1 2009;180(5):388-95. PMCID: PMC27427574. Park SW, Verhaeghe C, Nguyenvu LT, Barbeau R, Eisley CJ, Nakagami Y, Huang X,Woodruff PG, Fahy JV, Erle DJ. Roles of FOXA2 and FOXA3 in Allergic AirwayDisease and Asthma. Am J Respir Crit Care Med. Jul 23 2009 Oct 1;180(7):603-10.PMCID: PMC27537885. Dougherty RH, Sidhu SS, Raman K, Solon M, Solberg OD, Caughey GH, WoodruffPG, Fahy JV. Accumulation of intraepithelial mast cells with a unique proteasephenotype in T(H)2-high asthma. J Allergy Clin Immunol. 2010May;125(5):1046-1053.e8. PMC Journal – In Process6. Koth LL, Cambier CJ, Ellwanger A, Solon M, Hou L, Lanier LL, Abram CL,Hamerman JA, Woodruff PG. DAP12 is required for macrophage recruitment to thelung in response to cigarette smoke and chemotaxis toward CCL2. J Immunol. 2010Jun 1;184(11):6522-8. Epub 2010 Apr 26. PMC Journal – In Process7. Sidhu SS, Yuan S, Innes AL, Woodruff PG, Solon M, Hou L, Muller SJ, and FahyJV.Epithelial cell-derived periostin: roles in TGFbeta activation, collagen productionand collagen gel elasticity in asthma. Proc Natl Acad Sci U S A. 2010 Aug10;107(32):14170-5. PMCID: PMC2922596190

8. Choy DF, Modrek B, Abbas AR, Kummerfeld S, Clark HF, Wu LC, Fedorowicz G,Modrusan Z, Fahy JV, Woodruff PG, Arron JR. Gene expression patterns of th2inflammation and intercellular communication in asthmatic airways. J Immunol. 2011Feb 1;186(3):1861-9. PMC Journal – In Process9. Gordon ED, Sidhu SS, Wang ZE, Woodruff PG, Yuan S, Solon MC, Conway SJ,Huang X, Locksley RM, Fahy JV. A protective role for periostin and TGF-β inIgE-mediated allergy and airway hyper-responsiveness. Clin Exp Allergy. 2012Jan;42(1):144-55.10. Eri1 regulates microRNA homeostasis and mouse lymphocyte development andantiviral function. Thomas MF, Abdul-Wajid S, Panduro M, Babiarz JE, Rajaram M,Woodruff P, Lanier LL, Heissmeyer V, Ansel KM. Blood. 2012 Jul 5;120(1):130-42.Epub 2012 May 21.11. Jia G, Erickson RW, Choy DF, Mosesova S, Wu LC, Solberg OD, Shikotra A, CarterR, Audusseau S, Hamid Q, Bradding P, Fahy JV, Woodruff PG, Harris JM, ArronJR; Bronchoscopic Exploratory Research Study of Biomarkers inCorticosteroid-refractory Asthma (BOBCAT) Study Group. Periostin is a systemicbiomarker of eosinophilic airway inflammation in asthmatic patients. J Allergy ClinImmunol. 2012 Sep;130(3):647-65412. Solberg OD, Ostrin EJ, Love MI, Peng JC, Bhakta NR, Hou L, Nguyen C, Solon M,Nguyen C, Barczak AJ, Zlock LT, Blagev DP, Finkbeiner WE, Ansel KM, Arron JR,Erle DJ, Woodruff PG. Airway Epithelial miRNA Expression is Altered in Asthma.Am J Respir Crit Care Med. 2012 Sep 6. [Epub ahead of print]13. Huang F, Zhang H, Wu M, Yang H, Kudo M, Peters CJ, Woodruff PG, Solberg OD,Donne ML, Huang X, Sheppard D, Fahy JV, Wolters PJ, Hogan BL, Finkbeiner WE,Li M, Jan YN, Jan LY, Rock JR. Calcium-activated chloride channel TMEM16Amodulates mucin secretion and airway smooth muscle contraction. Proc Natl AcadSci U S A. 2012 Sep 17. [Epub ahead of print]Research SupportACTIVER01 HL097591 (Woodruff PG)7/1/2009 - 6/30/2013NIH/NHLBIRole of Th2 and non-Th2 Inflammation inAirway Smooth Muscle Remodeling in AsthmaThe goal of this study is to identify pathways linking Th2-driven inflammation to smooth muscleremodeling.R01 HL095372 (Woodruff PG)NIH/NHLBIMolecular Phenotyping of Asthma9/24/2008 - 7/31/2012No cost extension through 7/2013The goal of this study is to identify and characterize molecular phenotypes of asthma usinggene expression profiling, quantitative morphometry and related imaging techniques.191

HHSN268200900014C (Woodruff PG)2/1/2009 - 1/31/2016NIH/NHLBIThe Spiromics Project: Clinical CenterThe goal of this study is to identify sub-populations and intermediate outcome measuresin COPD through a large multi-center longitudinal study.P01 HL107202 (Fahy JV, Woodruff Core leader) 7/1/12-6/30/17NIH/NHLBIInnate and Adaptive Immune Responses in Th2 High AsthmaTo identify the roles of iH2 cells, IL-33 and miRNAs in local immune responses in the lung inasthma.2U19AI077439-06 (Sheppard D, Woodruff Core Leader, Project Co-I) 4/1/2013-3/31/18NIH/NIAIDIL-13 and IL-17 dynamics in the asthmatic airwayTo identify the cellular sources, tissue localization and local effects of IL-13 and IL-17 in thelung in asthma.R01 HL114447 (PI: Martinez, subcontract PI: Woodruff) 4/1/2012 - 3/31/2016NIH/NHLBIPulmonary bacterial microbiome-epithelial cell interactions in COPDThe goal of this study is to establish the lung microbiome in COPD and identify epithelial mucinresponses associated with selected pathogens.R21 HL108596 (Erle DJ, Woodruff Co-I)4/6/2011 - 3/31/2013NIH/NHLBIMicro-RNAs in Airway Epithelial Differentiationand AsthmaThe goal of this project is to understand how airway epithelial cell micro-RNAs functionand determine how these miRNAs contribute to asthma.U10 HL109146 (Fahy JV, Woodruff Co-I)7/1/2011 - 6/30/2017NIH/NHLBISevere Asthma Research ProgramThe goal of this project is to investigate molecular phenotypes and lectins that regulatemucus viscosity in severe asthma.U10 HL098107 (Boushey HA, Woodruff Co-I) 9/30/2009 - 6/30/2016NIH/NHLBIUCSF AsthmaNet Clinical CenterClinical Research Skills Development Core194

The major goals are to serve as a clinical center participating in the conduct of NHLBI-supportedmulti-center clinical trials of asthma therapies in children and adults with asthma, Role: Co-CoreLeaderR01HL110883 ((Kheradmand F, Woodruff sub Co-I) 2/15/2012-1/31/2016NIH/NHLBIAncillary T-Cell Based Studies in SPIROMICSThe major goals are to determine whether T-cell autoreactivity in COPD is associated withemphysema in cross-sectional and longitudinal human studies (using the Spiromics cohort).U10 RFA-HL-12-013 (Koth LL, Woodruff Co-I) 4/012012 – 3/31/15NIHI/NHLBIGenomic Phenotyping and Mechanisms in sarcoidosis and AATTo perform genomic and microbiomic human studies to define disease heterogeneity insarcoidosis and AATN01 AI90052 (Busse W, Woodruff subcontract) 9/30/2009- 9/29/14NIH/NIAIDInner City Asthma Consortium (ICAC): Immunologic Approaches to Reduce Asthma”To identify immunological approaches to reduction in asthma prevalence and severity in innercity populations.195