Cleveland Clinic Lerner Research Institute

Lerner Research Institute
Focusing on the Patients
of Tomorrow

A Legacy of Research
Focusing on the Patient
“It is through The Cleveland Clinic Foundation … that a continual policy
of active investigation of disease will be assured. That is to say, we are
considering not only our duty to the patient of today, but no less our duty
to the patient of tomorrow.”
George W. Crile, MD
Founder, Cleveland Clinic, at the opening of the first
Cleveland Clinic building on February 26, 1921
“It seems to me a pity
either to weaken or lose
the research approach to
the patients’ problems,
which has always been an
integral part of good medical
practice, or to lose the
humanitarian philosophy of
the good doctor.”
Irvine H. Page, MD
First Division Chair
(1945-1966)
“From the 1940s to the
late 1960s, the Division of
Research was a hub of advanced
laboratory and clinical
hypertension studies. It
wasn’t until the 1970s that
funding from the National
Institutes of Health [NIH]
became the prime source
of competitively awarded
research funding. Our
investigators, with proven
scientific innovations, were
well positioned to compete,
and one of the first successful
NIH awards was a large
program grant in hypertension
research.”
F. Merlin Bumpus, PhD
Division Chair
(1967-1984)
“From its founding, strong
research and education
were wrapped around the
Cleveland Clinic’s central
mission of better care for
the patient. Research programs
so designed and integrated
inspire and inform
scientists, no matter how
basic their research, to keep
their eyes on the patient’s
problems. With this vision,
and immersed in a powerful
ever-improving clinical environment,
research becomes
inherently translational
— and exciting. After all,
isn’t that why we invest in
medical research, why the
NIH has flourished and why
The Cleveland Clinic has
sustained its own special
quality on behalf of those
we serve?”
“A strong basic research
establishment is a vital
part of a strong academic
clinical institution. You can’t
have good translational
research without good basic
research.”
George Stark, PhD
Division Chair
(1992-2002)
Bernadine Healy, MD
Division Chair
(1985-1991)

Welcome
to the Lerner Research Institute
From its earliest days, Cleveland Clinic envisioned and encouraged an environment of discovery
and an atmosphere that fostered communication and collaboration among laboratory-based and
clinical researchers. Today, this philosophy and culture continues to serve Cleveland Clinic’s
mission – to provide the highest-quality patient care. The medical care available today would
not be possible without the research discoveries of the past. And today’s investigations pave
the way for new interventions and therapies that will have great positive impact on the lives of
patients of tomorrow.
Lerner Research Institute encompasses the complete breadth of research, from the laboratory
bench where discoveries are made to projects that translate those discoveries into new
treatments that are tested in clinical trials. For example, current research projects encompass
discovering new ways protein synthesis is regulated, identifying a new human virus,
determining the clinical effectiveness of new treatments for diseases, and designing evidencebased
decison models for physicians when treating prostate cancer, etc.
With 11 research departments and nearly 2,000 full-time employees, Lerner Research Institute
continues to grow in its stature as a premier biomedical research institute in the United States.
Our research strength is founded upon the fact that our investigators ask highly significant
and innovative questions that are focused on specific diseases. This approach encourages
laboratory-based and clinical researchers to work closely with each other – to share ideas,
observations and their diverse talents to effectively and efficiently translate discoveries into
world-class patient care.
We’ve expanded our research efforts in recent years into emerging areas that have a high
potential for novel ways to treat disease. We created the Genomic Medicine Institute, which
encompasses state-of-the-art genomics research, clinical care and counseling. The Department
of Stem Cell Biology and Regenerative Medicine was begun to take full advantage of this
promising field of medical research in identifying novel paradigms in the generation of cell types
and in the development of therapeutics to be used in the treatment of diseases that result from
the destruction of tissue.
The Institute’s investigators also play critical roles as faculty in two groundbreaking educational
programs: The Cleveland Clinic Lerner College of Medicine of Case Western Reserve University
and The Molecular Medicine PhD Program. Together, these programs train tomorrow’s clinicianscientists
and translational researchers who will lead the way in conducting biomedical
research.
We are committed to conducting world-class biomedical research, to speed delivery of new
therapies and treatments, and to maintain an environment of collegiality and multidisciplinary
collaboration.
Paul E. DiCorleto, PhD
The Sherwin-Page Chair
Institute Chair

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L e r n e r R e s e a r c h I n s t i t u t e
Lerner Research Institute Mission
MISSION STATEMENT
• Promote human health by investigating in the laboratory and the clinic the
causes of disease and discovering novel approaches to prevention and treatments
• Train the next generation of biomedical researchers
• Foster a culture that promotes productive, multidisciplinary collaborations
“As the home to laboratory-based, translational and clinical research, Lerner
Research Institute exemplifies the essential contributions that research makes to
patient care. The insights and understanding gained in the laboratory about the
underlying causes of diseases will create new diagnostic tools, treatments and
therapies. The Institute completes a cycle that continually advances laboratory and
clinical research, all the while keeping our patients at center stage – the main focus
and prime beneficiaries of its work.”
Delos M. Cosgrove, MD
Chief Executive Officer and President
Cleveland Clinic

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Lerner Research Institute Profile
• Total Research Budget: $272 million ($109M federal, $81M non-federal, $68M CCF internal,
$14M treasury)
• National Institutes of Health New Awards in 2009: $86 million
• Laboratory Principal Investigators: 200
• Total Employees: 2,000 (Full time-1,737)
• Laboratory and Clinical Research Space: 700,000 square feet
• Publications: 1,347 (1,223 journal articles, 116 book chapters and 8 books)
• Over the past five years, discoveries from LRI scientists generated 10 new companies,
73 patents and 53 licenses.
Total Research Full Time
Total Research Budget
Equivalents (FTE) Employees
(2005-2009)
(2005-2009)
Publications in Biomedical Journals
(2005-2009)
Discoveries
(2005-2009)

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L e r n e r R e s e a r c h I n s t i t u t e
Innovative Disease-Focused Research
2002-2009 Ohio Third Frontier Awards:
Top 10 Award-Winning Organizations
To create new and support existing jobs, The
State of Ohio Third Frontier funds innovative
research projects that can produce globally
competitive companies
Disease-Focused Research
Collaborations between basic-science researchers and clinicians encompass the full range
of medical research from the laboratory where discoveries are made to innovative projects
that translate those discoveries into clinical trials to impact patient care. Personalized
healthcare, stem cell biology and regenerative medicine are newly established areas of
expertise. Overall, laboratories focus on eight disease-focused groups:
% Research Projects Categorized by Disease Group
Neurologic
14%
Allergic &
Immunologic
11%
Musculoskeletal
10%
Metabolic
10%
Infectious 5%
Eye 3%
Cancer
23%
Cardiovascular
25%

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Education and Training
Mission: Research Education Office supports the administration, recruitment and
career development of postdoctoral fellows and graduate/undergraduate students
• Training Tomorrow’s Physician-Scientists: Cleveland Clinic
Lerner College of Medicine
• Training Tomorrow’s Basic Scientists in clinically-relevant
fields: Molecular Medicine PhD Program
• David and Lindsay Morgenthaler Endowed Fellowships
(to promote young independent fellows)
• McNair Scholars (to promote minority and disadvantaged
undergraduates to pursue PhD)
“Lerner Research Institute provides worldrenowned
research training opportunities
through PhD program partnerships with Case
Western Reserve University, Cleveland State
University, Kent State University, and the
University of Akron. In addition, Institute faculty
participation in our innovative, unique and
on-site Molecular Medicine PhD Program
and in the Cleveland Clinic Lerner College
of Medicine focuses on training both
MD and PhD students in basic and applied
research relevant to human health and disease.
Both of these top-ranked programs integrate medical
knowledge into graduate training and prepare
students for careers in bench-to-bedside research.
Through individualized advising efforts and formal
career development programs for medical and
graduate students and postdoctoral fellows and
undergraduate students, our faculty are creating a
legacy of outstanding research accomplishments.”
Marcia Takacs Jarrett, PhD
Director of Research Education
“I’m a little different from most students in
that I came into the CCLCM program already
with a basic-science PhD and postgraduate
training in the Institute’s Department of Cell
Biology. It has been an incredibly eye-opening
experience for me to learn of the vast pool of
clinical research opportunities. My training at
the Cleveland Clinic has not only given me
the skills to work directly with patients, but
to understand thoroughly how I can combine
both aspects of my training to optimize
translational research.”
Marie-Luise Brennan, PhD
Graduate, CCLCM Class of 2009
“The Lerner Research Institute serves as an ideal
training ground for students to learn to perform
medically-relevant research. Our innovative
Molecular Medicine PhD Program, supported by
the Howard Hughes Medical Institute, incorporates
a novel curriculum focused on integrating medical
knowledge into basic science education. Future
breakthroughs in treating diseases will come from
students trained in programs such as ours.”
Martha Cathcart, PhD
Director, Molecular Medicine PhD Program

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L e r n e r R e s e a r c h I n s t i t u t e
Heart Disease: A Major Killer
Areas of research: atherosclerosis, heart attacks, hypertension, heart
failure, abnormal heart rhythms
Recent Landmark Discoveries in Heart Disease
• Discovered an enzyme called myeloperoxidase (MPO) in blood that can increase the risk of coronary artery
disease – that led to a simple blood test that accurately predicts the likelihood of having a heart attack
• Unlocked how your body can use its own stem cells to regenerate heart tissue damaged during a heart attack
• Developed a mechanism by which smoking increases the risk of coronary artery disease –
providing new diagnostic tools
• Discovered novel micro-RNAs involved in human heart failure
• Described a mechanism by which a common genetic variation in a particular gene, corin, gives rise to hypertension
• Discovered that an alternative splicing program is important in embryonic formation of heart valves and septaunderstanding
its regulation will help elucidate molecular mechanism that cause cardiac birth defects
• Discovered a “heart attack gene” that links a genetic mutation to greater risk for heart attacks
Grant Highlights
• Edward Plow, PhD, Chair, Molecular Cardiology, is heading a $17.5 million specialized center grant
on the molecular determinants of coronary artery disease
“It would appear that stem cells may tire out over
time. There’s evidence that aging does play a role
in stem cell function. Now we’re trying to determine
if it’s the heart not sending out the message
to stem cells, or the stem cells not responding to
the signal. The heart needs to grow new vessels
to nourish the new cells. But if the stem cells
aren’t getting to the heart, the heart dilates and
the patient develops heart failure in response to
aortic stenosis.”
Marc Penn, MD, PhD
Stem Cell Biology and Regenerative Medicine
Qing Wang, PhD
Molecular Cardiology
“We found a genetic
mutation, linked to atrial
fibrillation, in a family
with a history of sudden
death in their children.”
12h
48h
24h
72h
The beneficial effects of stem cell transplantation
after heart attack are mediated
primarily through preservation of cells. In
this experiment from Dr. Penn’s lab, heart
cells are stained to show Troponin I (red),
cell nuclei (blue) and the survival receptor
CXCR4 (green). Cells increased expression
of CXCR4 72 hours after stem cell transplantation
following a heart attack.
A newly discovered gene,
NUP155, which causes
atrial fibrillation when
mutated. NUP155 is a
non-ion channel gene that
makes a protein component
of the nuclear pore
complex (NPC, white
arrows), located at the
nucleus of a cell.

Heart Disease: A Major Killer
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“We looked at more than 600 sequential patients who
came to the emergency rooms with chest pain. We found
that adding MPO testing to current laboratory-based risk
assessments increased our ability to predict future cardiac
risks over the next 30 days to six months from 50% to
95% of the time.”
Stanley Hazen, MD, PhD
Cell Biology
Director, Cardiovascular Diagnostics & Prevention
Dr. Wu discovered the protease called
corin, which is expressed in the heart
and is associated with heart failure.
Qingyu Wu, PhD
Molecular Cardiology
Sadashiva Karnik, PhD
Molecular Cardiology
Sathyamangla Naga Prasad, PhD
Molecular Sathyamangla Cardiology Naga Prasad, PhD
Molecular Cardiology
Drs. Karnik and Prasad led a team of investigators in discovering novel microRNAs (miRNA) involved in
human heart failure. This figure is a map of significantly altered miRNAs from individual patient samples
from non-failing human hearts and failing human hearts diagnosed with dilated cardiomyopathy.

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L e r n e r R e s e a r c h I n s t i t u t e
Thrombosis
Areas of research: vascular biology, vitamin K and platelet biology,
cell adhesion and aggregation, extracellular matrix proteins
Recent Landmark Discoveries in Thrombosis
• Found that Migfilin, a cytoskeletal adaptor, acts as a molecular switch for regulating integrin
activation and adhesion
• Discovered a protein that causes platelets to become hyperactive, leading to an increased risk
of forming blood clots
• Discovered mutation in KINDLIN-3 gene that causes a previously unrecognized disease,
Integrin Activation Deficiency Disease, in humans
Grant Highlights
• Edward Plow, PhD, Chair, Molecular Cardiology, and Roy Silverstein, MD, Chair, Cell Biology, are each
heading individual program project or specialized center grants in thrombosis, focusing on the structure and
function of beta-3 integrins ($9.7 million) and genetic determinants of arterial thrombosis ($13.2 million)
Dr. Plow’s expertise in cell
adhesion, aggregation and
spreading are critical aspects
of atherosclerosis plaque
development and thrombosis.
Edward Plow, PhD
Chair, Molecular Cardiology
Dr. Qin solved the molecular structure
of the integrin-activator talin
(in green) bound to the integrin
αIIbβ3 (in blue/red) found on
platelets. The binding induces the
complex to dissociate, which
leads to platelet aggregation
and blood clot formation.
Jun Qin, PhD
Molecular Cardiology
Platelets and white blood cells
aggregate when exposed to cigarette
smoke, increasing the risk of stroke
and heart attacks.
Thomas McIntyre, PhD
Cell Biology

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Atherosclerosis
Areas of research: Lipoprotein oxidation and metabolism, homocysteine
metabolism, genetics of atherosclerosis, inflammation
Recent Landmark Discoveries in Atherosclerosis
• Indentified candidate genes that modify atherosclerosis severity in mice, and common human variations in
these genes associated with coronary artery stenosis
• Found that apo(a), a cardiovascular risk factor, acts as a natural suppressor of inflammation
• Indentified two enzymes that direct white blood cells to migrate to sites of inflammation on blood vessels
Grant Highlights
• Paul DiCorleto, PhD, Institute Chair, heads the longest-running program project grant in the LRI (27 years)
examining inflammatory responses in vascular cells, attracting a total of $41.6 million
• Stanley Hazen, MD, PhD, and Roy Silverstein, MD, Chair, Cell Biology, each lead individual program
project or specialized center grants studying oxidation in inflammation ($9 million) or in phospholipids
($11.4 million) as it pertains to cardiovascular disease and pathology
“We’re among the top institutions in
the world for cardiovascular research,
and without research there would be
less ability to recruit the best clinicians
and less recognition for our world-class
patient care. Today, most people who
have heart attacks can expect to live
long lives. Discoveries made in laboratories
… contribute to that success.”
Roy Silverstein, MD
Chair, Cell Biology
Dr. Smith is discovering the
genes that increase the risk
of developing atherosclerosis,
focusing on genes located on
chromosome 17, which are
associated with a model that
develops atherosclerosis.
Jonathan Smith, PhD
Cell Biology
Dr. Cathcart is researching the role of
chronic inflammation in atherosclerosis
induced by the white blood cells called
monocytes.
Martha Cathcart, PhD
Cell Biology

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L e r n e r R e s e a r c h I n s t i t u t e
Cancer – A Future of Great Promise
Areas of research: oncogenesis, apoptosis and cell death, proliferation,
angiogenesis, tumor biology of the brain, breast, colon, lung, prostate and kidney
Recent Landmark Discoveries in Cancer
• Delineated the role of Dab2 in tumor suppression
• Identified the role of reactive oxygen species produced during cytokine therapies used in human diseases,
which may potentially explain negative side effects
• Defined a novel role for cyclin E, a regulator of dividing cells, which in tumor cells is cleaved to produce a
protein (p18-cyclin E) that induces apoptosis or cell death. This cleaved protein may be used as a marker
to gauge successful cancer therapies
• Discovered an “RNA switch” that regulates the expression of vascular endothelial growth factor (VEGF), an
important factor in normal and pathological blood vessel development. This switch represents a new target
for development of pharmacologic therapy against cancer
“The cure to cancer has been notoriously elusive, but new technology is shedding
light on why not all individuals respond in similar ways to similar treatments,
giving us better insight than ever into causes and potential cures.”
Janet Houghton, PhD
Chair, Cancer Biology
Dr. Janet Houghton’s research approach uses tumor samples
from cancer patients to identify causes and potential cures
through rational preclinical design
Find differentially
expressed genes
Detailed pathway and
network analysis
In vitro target
validation
Dr. Byzova is studying the role of pathological
angiogenesis (new blood vessel
formation) that plays a role in feeding the
unrestrained growth of tumors.
Tatiana Byzova, PhD
Molecular Cardiology
Director, Angiogenesis Research Center
Dr. Howe studies transforming
growth factor beta (TGFbeta),
which exerts antiproliferative
effects and functions as a tumor
suppressor during early stages of
tumorigenesis, whereas at later
stages it functions as a tumor
promoter aiding in metastatic
progression.
Phillip Howe, PhD
Cancer Biology

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Brain Tumor Research
Areas of research: gliomas, surgical advances, clinical trials, etiology
and pathogenesis, stem tumor cells, molecular markers
Recent Landmark Discoveries in Brain Tumor Research
• Developed a laser technique to kill inoperable brain tumors
• Developed an optical detection method for tumors using fluorescent nanoparticles
• Together with University Hospitals Case Medical Center, began clinical trials on a vaccine against
glioblastomas, the most aggressive type of brain tumor
“The Cleveland Clinic Brain Tumor
and Neuro-Oncology Center’s physicians
and scientists collaborate with
other academic institutions and with
pharmaceutical companies to translate
advances in brain tumor laboratory
research into potentially effective new
therapies for the incurable diseases
that we treat.”
Gene Barnett, MD
Director, Brain Tumor and
Neuro-Oncology Center
Human glioma (brain tumor) cells that over-express the
fluorescent protein EGFP are growing in a mouse brain.
This xenograft is used to develop various strategies to
deliver active tumor-killing drugs to these cells.
Michael Vogelbaum, MD, PhD
Director, Center for Translational Therapeutics Associate
Director, Brain Tumor and Neuro-Oncology Center
Angiogenesis (new blood vessel growth) is
a highly characteristic feature of glioblastoma
tumors. Angiogenesis (brown stain)
contributes to the poor median survival
(18 months) of patients with this tumor.
Dr. Gladson is studying new agents
that target angiogenesis in glioblastoma
tumors.
Candece Gladson, MD
Cancer Biology

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L e r n e r R e s e a r c h I n s t i t u t e
Personalized Medicine for
Preemptive Cancer Treatment
Recent Landmark Discoveries in Personalized Medicine for Cancer
Treatment
• Discovered RNase L, which inhibits prostate cancer and viral infections
• Discovered alterations in the cancer gene, PTEN, that increases the risk of breast and
thyroid cancer by 3-10 fold
“Finding mutations or alterations in cancerpredisposing
genes can lead to preemptive
strikes and prevention of genetic risks of
various cancers.”
Charis Eng, MD, PhD
Chair, Genomic Medicine Institute
“The American Cancer Society estimates
that infections cause almost
20% of all cancers worldwide, accounting
for an estimated 1.9 million
cases per year. The most common
infectious agents for cancer are viruses
such as human papillomavirus and
hepatitis C virus. We found that a
tumor suppressor gene called RNASEL
or HPC1 has dual functions in both
inhibiting hereditary prostate cancer
and viral infections.”
Robert Silverman, PhD
Cancer Biology
Dr. Maciejewski has Identified unique missense
mutations in the c-Cbl gene associated with
myeloid malignancies.
Jaroslaw Maciejewski, MD, PhD
Chair, Translational Hematology and Oncology Research
The human retrovirus (XMRV) was discovered in tumor-bearing prostates
of men with RNASEL mutations. Shown (from upper left, clockwise) is
the domain structure of RNase L with its activator 2’-5’-oligoadenylate, a
model of RNase L with RNA substrate, a small molecule drug candidate
docked with RNase L, a genomic map of XMRV, diagram of tumor in
the peripheral zone of prostate, and fluorescence in situ hybridization
(white arrow) of XMRV in prostate stromal cell.

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Women’s Health
Areas of research: alternative splicing in gender-specific gene expression,
premature ovarian failure, pelvic floor disorders, autoimmunity, cardiac
dysfunction, sports medicine
Recent Landmark Discoveries in Women’s Health
• Developed gender-specific models of heart disease and failure
• Developed diagnostic devices to make accurate and timely diagnosis of pelvic floor prolapse
• Developed biomechanics-based computer simulation of women’s sports-related injuries
Dr. Vincent Tuohy has developed a vaccine that provides
safe and effective protection against growth of breast tumors
in several mouse models. Remarkably, this protection occurs
in the complete absence of any detectable side effects and
is now being tested to determine if normal cancer-free women
can be safely protected from developing breast cancer.
Vincent Tuohy, PhD
Immunology
Inhibition of autochthonous breast tumor
growth in MMTV-neu mice vaccinated with
the proprietary target test protein.
The heart from a female transgenic mouse (right)
next to a heart from a normal female (left) showing
the heart disease phenotype that we see when we
disrupt alternative splicing in the heart muscle.
Andrea Ladd, PhD
Cell Biology

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L e r n e r R e s e a r c h I n s t i t u t e
Inflammatory Diseases
Areas of research: gene expression, adaptive immunity, systemic lupus
erythematosus, inflammatory bowel disease, organ transplantation,
immunology of cancer
Recent Landmark Discoveries in Inflammation
Inflammatory Diseases
• Identification and characterization of specific chemoattractant peptides in regulating inflammation and
trafficking to sites of organ transplantation
• Identification and characterization of the signal pathways necessary for the action of interleukin-17,
a major pathogenic pro-inflammatory cytokine
• Demonstration that negative regulation of Toll-like receptor inflammatory signaling in the gut
contributes to cancer
• Identification of autoimmune involvement in causing cardiomyopathy, hearing loss and premature
ovarian failure
• Identification of mechanisms governing the ability of tumors to avoid and even re-direct the immune
system from anti-tumor to pro-tumor activity
Grant Highlights
• George Stark, PhD, leads a program project grant ($10 million) on interferons and cytokine signaling,
which are key pathways in inflammation
“Disturbances in the regulation of inflammatory
response is a major contributing feature of most
disease pathogenesis. One of our major objectives
is to identify the fundamental mechanisms
that govern these processes as this information
has enabled the development of important
new therapeutic interventions in cancer, heart
disease and multiple autoimmune disorders.”
Thomas Hamilton, PhD
Chair, Immunology
SEFIR 17RA
SEFIR 17RC
Act1 SEFIR
TRAF6
Ubc13/
Uev1A
“In collaboration with Drs. Tom Hamilton, Vince Tuohy and Mark
Aronica, we discovered a novel protein [Act-1] involved in inflammation
that may be a critical mediator of rheumatoid arthritis,
inflammatory bowel disease, as well as allergy responses.”
Xiaoxia Li, PhD
Immunology
TRAF6
Ubc13/
TAB2/3
Uev1A
TAK1
NEMO
IKKα IKKß
NFB

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Inflammatory Diseases
Grant Highlights
• Dr. Nagy is heading a $2.3 million P20 Center grant on alcoholic liver disease
Laura Nagy, PhD
Gastroenterology and Pathobiology
The activation of complement by alcohol
contributes to alcoholic liver disease.
Dr. Fox discovered a translational control
pathway involving Interferon-Gamma-
Activated Inhibitor of Translation (GAIT)
complex (above) that selectively regulates
inflammatory gene expression. This pathway
may play a critical role in resolving
inflammation.
Paul Fox, PhD
Cell Biology

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L e r n e r R e s e a r c h I n s t i t u t e
Inflammatory Bowel Disease
“Both forms of Inflammatory Bowel Disease (IBD) [Crohn’s
disease and ulcerative colitis] are clinically serious conditions
whose incidence is rapidly increasing worldwide. Their pathophysiology
is still incompletely understood because of the
multiplicity and complexity of the factors involved, including
environmental changes, genetic predisposition and an abnormal
immune response against the gut commensal flora. IBD
research has made great strides in the last couple of decades,
but much more work is needed to unravel its pathogenesis and
develop better and more specific forms of therapy.”
Claudio Fiocchi, MD
Pathobiology
Microarray and network analysis
of primary human intestinal
microvascular endothelial cells
that have transformed under
the influence of the pro-inflammatory
molecules generated in
inflamed IBD tissue.
Mononuclear leukocytes (red/
blue circles) bind to specific
hyaluronan cable structures
(green) on colon mucosal
smooth muscle cells, leading
to increased inflammation,
which is a characteristic
pathology of inflammatory
bowel disease.
Carol de la Motte, PhD
Pathobiology

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Organ Transplantation
The total surface area of the face allograft
was 536 square centimeters. The surgery
integrated different functional components,
such as nose, lower eyelids, upper lip,
skin, muscles, bone, infraorbital floor,
bilateral zygomas, anterior maxilla with
total alveolus anterior hard palate, and
arteries, veins and nerves.
“…No other aspect of our anatomy is
capable of the complexity of motion and
emotion allowed by the muscles and
tissues of the face…”
Maria Siemionow, MD, PhD
Director of Plastic Surgery Research
Dr. Siemionow led a team of six surgeons
in a 22-hour surgery and performed the
first near-total face transplant in the
U.S. in December 2008.
Analysis of kidney transplant grafts from
recipients who rejected (A, B, and C) or
accepted (D, E, and F) the transplant.
Inflammatory cells, edema and hemorrhage
(arrows) are common in rejected tissue.
Robert Fairchild, PhD
Immunology

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L e r n e r R e s e a r c h I n s t i t u t e
Infectious Disease
Areas of research: vesicular stomatitis virus, human parainfluenza virus,
RNA viruses, malaria, vaccines, antiviral medications
Recent Landmark Discoveries in Infectious Diseases
• Discovered a new biosynthetic pathway in the life-cycle of a virus related to Ebola, rabies and measles,
opening the search for drugs to stop their ability to multiply and spread
• Discovered a way to “sort out” cells in the blood that have malaria from normal blood cells as a means to
rid the body of infection
• Began small molecule screening for antiviral drugs against human parainfluenza virus type 3, a virus that
attacks infants and children but currently has no vaccines or antivirals available
• Discovered a new human retrovirus, xenotropic murine leukemia virus-related (XMRV), in tumor-bearing
prostate tissues
Vesicular stomatitis virus
“Our primary research goal is to explore and
establish the various biosynthetic pathways by
which the viruses multiply in a host cell. Thorough
understanding of these pathways is vital to develop
and design drugs to arrest their multiplication. Our
continued effort in this area has unfolded several
unique viral pathways and interactions with host
proteins which are currently being used as targets
for drug action.”
Amiya Banerjee, PhD
Molecular Genetics
Head, Section of Virology
Maciej Zborowski, PhD,
Biomedical Engineering,
is pioneering the use of
magnets to sort out cells
infected with the malaria
parasite.

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Diabetes – a U.S. Epidemic
Areas of research: stem cells and pancreatic regeneration, glucoseregulated
gene expression, insulin resistance, biomarkers, type 2
diabetes, fatty liver disease, vascular complications of diabetes,
physiology of obesity
Recent Landmark Discoveries in Diabetes
• Discovered that a receptor for toxic hydrocarbons, such as in tobacco smoke or herbicides, also mediates
the damaging effects of diabetes in blood vessels
• Uncovered the mechanism of why high glucose levels can increase the expression of proteins that damage
blood vessels, a common cause of death in diabetes
• Found that elevated plasma ceramide levels may be a biomarker of insulin resistance, atherosclerotic
risk and/or damage obesity-induced inflammation
• Discovered that FGF10, a factor that regulates growth, can be used to maintain stem cell progenitors
in the pancreas and may be useful in programs to regenerate the gastric system
• Discovered a receptor on fat cells and macrophages that links oxidative stress and hyperlipidemia
to insulin resistance
“Our hope is that pancreatic precursors may be
modulated to replace insulin-producing beta cells
in patients with diabetes.”
Jan Jensen, PhD
Stem Cell Biology and Regenerative Medicine
Director, Center for Diabetes Research
Olga Stenina, PhD,
Molecular Cardiology,
uncovered how high
glucose levels cause
damage to blood
vessels.
A WT B TG
E14.5
FGF10 signaling controls stomach progenitor maintenance, morphogenesis and cellular
differentiation. Normal gastric organ formation (A) was disrupted in transgenic mice in which the
FGF10 gene was disrupted (B).

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L e r n e r R e s e a r c h I n s t i t u t e
Neurodegenerative Disease
Areas of research: Parkinson’s disease, multiple sclerosis, Alzheimer’s
disease, epilepsy, and other movement disorders
Recent Landmark Discoveries in Neuroscience
• A major discovery of a possible casual link between mutations in the TDP-43 gene and Amyotrophic
Lateral Sclerosis, or Lou Gehrig’s Disease
• Discovery of novel proteins involved in Alzheimer’s disease that may be regulated for new therapeutics
• Discovery of a neural stem cell that can regenerate myelin, a key brain structure that is damaged in
multiple sclerosis
• A drug previously used in cancer therapy can improve muscle function in a mouse model of Duchenne
dystrophy, the most common and lethal genetic muscle disease
• Discovery that the aberrant migration of immature neurons in the fetal brain caused by maternal alcohol
consumption may be corrected by controlling the activity of key signaling pathways
• Discovery of a biomarker that can determine the effectiveness of therapeutic strategies to reduce or
eliminate amyloid beta deposition, which may play a causative role in Alzheimer’s disease pathogenesis
“The Institute is a magnet for talented investigators.
We attract and retain some of the best researchers
in the world. That’s allowed us to develop very
strong programs focused on human neurodegenerative
diseases.”
Bruce Trapp, PhD
Chair, Neurosciences
“Targeting reticulon-3 aggregation, which occurs
naturally in the elderly brain, may offer a novel
therapeutic regime to reduce cognitive decline in
our expanding elderly population and in Alzheimer’s
patients.”
Riqiang Yan, PhD
Neurosciences
Reticulon-3 plaques (green) among
neurons (red) in the Alzheimer brain.

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Neurodegenerative Disease
Grant Highlights
• Richard Ransohoff, MD, leads a program project grant ($5 million) on inflammation and tissue injury in
multiple sclerosis
• Cornelia Bergmann, PhD, leads a program project grant ($8 million) on the regulation of CNS viral persistence
Dr. Ransohoff’s research focuses on chemokine
receptor expression that regulate leukocyte or white
blood cell migration in brain inflammation. This
image shows two chemokine receptors (one red,
the other green) and their location in the brain.
Elucidating mechanisms of brain inflammation may
be useful for understanding the pathogenesis of
disorders including multiple sclerosis (MS), brain
and spinal cord trauma, stroke, and HIV infection.
Richard Ransohoff, MD
Neurosciences
Neuroinflammation Research Center
Dr. Cameron McIntyre builds detailed computer models of deep brain stimulation (DBS). These models
enable analysis of the neuroanatomy and electrode location in the brain. (A) Stereotactic coordinate
system was defined relative to the imaging data. (B) Microelectrode recording data were entered into
the model (thalamic cells, yellow dots; subthalamic cells, green dots; substantia nigra cells, red dots).
(C) Three-dimensional brain atlas was fitted to the neuroanatomy and neurophysiology (yellow volume,
thalamus; green volume, subthalamic nucleus). (D) DBS electrode was positioned in the model. (E)
Theoretical ellipsoid target volume was used to define optimal stimulation parameter settings.
Cameron McIntyre, PhD
Biomedical Engineering

22
L e r n e r R e s e a r c h I n s t i t u t e
The Fight Against Blindness
Areas of research: inherited retinal diseases, glaucoma, macular
degeneration, corneal repair and transplantation, retinal physiology,
diabetic retinopathy, and vision restoration
Recent Landmark Discoveries in Ophthalmic Research
• Identified oxidative protein modifications in ocular tissues and plasma that may contribute to age-related
macular degeneration (AMD) and provide biomarkers of AMD risk and susceptibility
• Generated an AMD-like phenotype in mice immunized with lipid-derived oxidative protein modifications
• Prevented oxygen-induced retinopathy, similar to a retinal disease of severely premature infants, in a model
using a drug that blocks the loss of hypoxia-inducible factor
“We are mapping out the early events
that may cause macular degeneration,
the most common type of blindness in
our aging population, which may lead
to novel treatments.”
Joe Hollyfield, PhD
Cole Eye Institute
Vascularization of the eye
Macular degeneration of the eye
“Oxygen-induced retinopathy is characterized
by an area of central blood vessel
loss (arrow, top figure). We found that
injection of human umbilical cord blood
derived CD133+ progenitor cells rescued
retinal damage by promoting repair of
the vasculature (bottom figure).”
Bela Anand-Apte, MBBS, PhD
Cole Eye Institute

2 0 1 0 23
Tissue Regeneration
Areas of research: bone, wound joint and skin repair/regeneration, stem cells
Recent Landmark Discoveries in Tissue Regeneration
• Artificial skin model
• Use of stem cells to repair bone fractures
• Targeting stem cells to treat cancers
“The beauty of stem cells is their nearly endless supply and their ability to become the type of
cells they are derived from. A single stem cell should be able to create an entire tissue, opening
the door to an amazing ability to regenerate and repair damaged organs. Lerner Research Institute
is perfectly positioned to help with the thoughtful application of stem cells to healthcare that will
hopefully provide effective and ethical methods to improve the well-being of patients.”
Jeremy Rich, MD
Chair, Stem Cell Biology & Regenerative Medicine
“Cord blood stem cells are an important resource that
we will find uses for. They represent an untapped opportunity
for future care, but their use requires us to be
able to measure the number and quality of stem cells
and their potential if transplanted elsewhere. These are
cells we can be using very soon.”
George Muschler, MD
Biomedical Engineering
Director, Clinical Tissue
Engineering Center
A. Cluster or colonies of bone-forming-cells
(stained red) can be seen on this porous
bone scaffold after nine days in culture.
These are formed by individual osteoblastic
progenitor cells that rapidly attach to this
material and then proliferate. B. Two weeks
after a fracture, cells expressing alkaline
phosphatase (red), which are making new
bone and cells that have come from blood
(green), contribute to fracture repair. C.
Individual cells that have attached to a thin
sheet of bone matrix can be seen as brightly
fluorescent points across the surface.

24
L e r n e r R e s e a r c h I n s t i t u t e
Clinical Research
Dr. Lincoff supervises clinical research activities throughout the Cleveland Clinic as Director of the
Center for Clinical Research. He is also director of C5Research, an academic research organization
which plans, coordinates and manages multicenter clinical trials of new pharmacologic therapies.
Dr. Lincoff’s research activities focus on development of therapies to reduce acute and long-term
complications of coronary revascularization, to optimize therapy for acute coronary ischemic
syndromes, or reduce progression or complications of atherosclerosis.
A. Michael Lincoff, MD
Director, Center for Clinical Research
Director, C5Research (Cleveland Clinic Coordinating Center for Clinical Research)
Vice-Chair, Cardiovascular Medicine
“In Quantitative Health Sciences, we are beginning the process of providing interactive risk
calculators, so that these predictions of health risks become readily available to physicians in
their treatment of the patient [www.clinicriskcalculators.org]. Patients need accurate and tailored
predictions of their health outcomes they should expect in the future, as a consequence of the
healthcare choices they must make today.”
Michael Kattan, PhD
Chair, Quantitative Health Sciences
Dr. Janigro’s research focuses on the blood-brain-barrier (BBB) and how small vessel ischemic
disease (A, SVID) and brain cancer (B, metastasis) can produce leakages in the BBB, which
causes problems in assessing markers of brain cancer, especially in elderly patients who
commonly suffer from SVID.
Damir Janigro, PhD
Cell Biology
Director, Center for
Cerebrovascular Research

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Clinical Research
Grant Highlights
• Serpil Erzurum, MD, Chair, Pathobiology, leads a program project grant ($9.6 million) on the
pathobiology of asthma
“Our clinical research program has always been strong, but it really moved forward when we received
one of only 38 Clinical and Translational Science Awards [CTSA]. The guiding vision of the CTSA is to
provide premier clinical and translational research support and infrastructure so that our researchers
can provide national and international leadership for the treatment, cures and prevention of human
diseases. Our CTSA enables our physician-scientists and laboratory-based scientists to routinely test
and translate their discoveries through innovative approaches that characteristically involve patients.
We think of our [clinical research] participants as equal partners in the CTSA. Without them we could
never advance medical care.”
Serpil Erzurum, MD
Chair, Pathobiology
Director, Clinical Research Unit
Dr. Erzurum showed that angiogenesis (new blood
vessel formation) is a primary event in asthma that
occurs prior to the initiation of airway inflammation.
Following an allergen-challenge in an individual,
endothelial progenitor cell (EPC) mobilization occurs
within hours, and the circulating EPCs are recruited
into the challenged lungs. EPC recruitment and interaction
with pulmonary tissue results in the release
of mediators that drive angiogenesis and recruitment
of eosinophils, setting the stage for chronic airway
inflammation.

26
L e r n e r R e s e a r c h I n s t i t u t e
Clinical Research
“The leading cause of death in the U.S. is heart disease, and the creation of
an internationally recognized Global Cardiovascular Innovation Center (GCIC)
will help the Cleveland Clinic to continue to develop life-saving technologies
and treatments.”
Steven Nissen, MD
Chair, Cardiovascular Medicine
Principal Investigator, GCIC grant
The GCIC (artist rendering) is a $250 million
research and product development consortium
(planned opening in 2010) that received $60
million from the State of Ohio’s Third Frontier
Project.

2 0 1 0 27
Medical Devices
Recent Landmark Medical Devices
• Stents to treat aortic aneurysms
• Total artificial heart
• Cardiac assist devices
• Bioprosthetic valves
• Use of robots for stroke therapy
Dr. Golding, together with David Horvath, Senior
Principal Research Engineer, developed the prototype
of the Total Artificial Heart Program’s “continuous flow
total artificial heart,” which is about the size of an
adult’s fist, with a single moving part and capable of
smoothly and noiselessly pumping six liters of fluid per
minute. Ultimately, it will be made of titanium with a
10-year life.
Leonard Golding, MD
Biomedical Engineering
Dr. Alberts is currently conducting a preliminary clinical trial to determine the
effectiveness of using a robotic device as an adjunct to traditional physical
therapy in the rehabilitation of the upper extremity of patients who have
suffered a stroke.
Jay Alberts, PhD
Biomedical Engineering

28
L e r n e r R e s e a r c h I n s t i t u t e
Our Research Focuses
on the Patients of Tomorrow
Today’s Research for Tomorrow’s Cures-Current Focus Areas
• First clinically-long term bioartificial kidney
• Nanomedicine and microdevices
• Translational studies using stem cells to cure diseases – such as diabetes, bone loss, brain damage, spinal
cord injuries and heart failure
• Personalized healthcare – predicting a patient’s predisposition to diseases and treatments through
genomics-based research and screening
• Algorithms that assess patient outcomes to assist clinicians with optimized treatment options
• Electronic Nose (ENose) to detect lung cancer by breath analysis
“Our laboratory discoveries today represent
the new therapies, the new drugs, and the
new treatments for patients five, ten, fifteen
years from now. In a sense, our mission in
the Lerner Research Institute is to treat the
patients of tomorrow.”
Paul E. DiCorleto, PhD
Institute Chair
A close-up of the new siliconbased
membrane (top) and a
conventional dialysis membrane
(bottom) used to make the
bioartificial kidney
Scanning electron microscope images of polydimethylsiloxane smooth and textured
surfaces used to attach cell populations in regenerative tissue engineering

Paul E. DiCorleto, PhD
Institute Chair
9500 Euclid Avenue/NB21
Cleveland, OH 44195
216.444.3900
www.lerner.ccf.org
For comments or questions
regarding this brochure,
contact: Lri-contact@ccf.org