11:10-12:00, Rm 103

KMA Plenary LectureNuclear receptor regulation of nutrient metabolismDavid J. MangelsdorfDepartment of Pharmacology and Howard Hughes Medical Institute, U.T. Southwestern MedicalCenter at Dallas, Texas, USAMoosa Plenary LectureTargeting angiogenesis and lymphatic metastasisKari Alitalo and collaboratorsMolecular/Cancer Biology Laboratory, Haartman Institute and Finnish Institute for MolecularMedicine, Biomedicum Helsinki, P.O.B. 63, 00014 University of Helsinki, FinlandThe ability to regulate nutrient metabolism under conditions of excess (i.e., after a bigmeal) or deprivation (i.e., starvation) is a physiologic process that coincided with theevolution of nuclear receptors in all multi-cellular organisms. In mammals, nuclearreceptor systems have evolved to respond to cholesterol, bile acids, and fatty acids andthereby govern nutrient metabolism in the fed and fasted state. Recently, we havediscovered that this process is conserved in nematodes, and this has led to the discoverythat nuclear receptor regulated pathways may be exploited therapeutically to target twounexpectedly related human diseases: type 2 diabetes and nematode parasitism.Plenary LectureNF-κB, immunity and inflammationSankar GhoshDepartment of Microbiology & Immunology Columbia University, College of Physicians &Surgeons 701 W. 168th Street, HHSC 1210 New York, NY10032, USAThe transcription factor NF-κB is critical for the inducible expression of many genesinvolved in the innate immune and inflammatory responses. NF-κB plays an importantrole in these processes by augmenting the expression of many inducible genes includingIL-1, IL-6, IL-8, TNF-α, IFN-β, GM-CSF and serum amyloid A protein. Understanding howdifferent signals such as TNF-α, IL-1 or LPS lead to the activation of NF-κB has been atopic of great interest. It has also become clear that regulation of gene expression bytranscription factors such as NF-κB is influenced by epigenetic factors that regulatechromatin structure and accessibility. In this presentation I will present our recent findingsabout the mechanisms that regulate NF-κB in inflammation and immunity.Vascular endothelial growth factor (VEGF) stimulates angiogenesis and permeability ofblood vessels via its two receptors VEGFR-1 and VEGFR-2, but it has only littlelymphangiogenic activity. The third receptor, VEGFR-3, does not bind VEGF and itsexpression becomes restricted mainly to lymphatic endothelia during development.Homozygous VEGFR-3 targeted mice die around midgestation due to failure ofcardiovascular development, whereas transgenic mice expressing the VEGFR-3 ligandVEGF-C or VEGF-D show evidence of lymphangiogenesis and VEGF-C knockout micehave defective lymphatic vessels. VEGF-C provides effective treatment of lymphedema,even in a genetic mouse model where VEGFR-3 is mutant (Milroy’s disease). Theproteolytically processed form of VEGF-C binds also to VEGFR-2, as we have recentlyshown in crystal structure analysis, and is angiogenic and in vivo. Thus VEGF-C andVEGF-D appear to provide both angiogenic and lymphangiogenic activity. VEGF-Coverexpression induces capillary lymphangiogenesis and growth of the draining lymphaticvessels, intralymphatic tumor growth and lymph node metastasis. Furthermore, solubleVEGFR-3 and antibodies blocking VEGFR-3 inhibit embryonic and tumorlymphangiogenesis and lymphatic metastasis. These results have indicated that paracrinesignal transduction between tumor cells and the lymphatic endothelium is involved inlymphatic metastasis. - We have recently found a role for VEGFR-3 signaling also insettings of physiological and pathological angiogenesis. VEGF-C and VEGFR-3 blockingantibodies provided significant inhibition of tumor angiogenesis and growth and theyimproved tumor growth inhibition by anti-VEGF therapy. Enhanced VEGFR-3 expressionwas often detected in endothelial sprouts, and blocking of VEGFR-3 signaling inhibitedangiogenic sprouting. Blocking of the Notch signaling pathway lead to widespreadendothelial VEGFR-3 expression and excessive angiogenesis, which was inhibited byblocking VEGFR-3. The Notch pathway and the PDZ domain protein CLP24 that interactswith the VEGFR-2 and VEGFR-3 pathways were also shown to regulate lymphatic vesselgrowth and development. - Our studies indicate that VEGF-C and VEGFR-3 provide newtargets to complement current anti-angiogenic therapies. Furthermore, our studiesindicate that antibody combinations may be used for increased efficacy of inhibition ofangiogenic signal transduction pathways.Tammela, T. et al., Blocking VEGFR-3 suppresses angiogenic sprouting and vascularnetwork formation. Nature 454:656-60, 2008.Leppänen et al., Structural determinants of growth factor binding and specificity by VEGFreceptor 2. Proc. Natl. Acad. Sci. USA, 107: 2425-30, 2010.Saharinen P. et al., Claudin-like protein 24 interacts with the VEGFR-2 and VEGFR-3pathways and regulates lymphatic vessel development. Genes Dev. 24:875-80, 2010.Tammela T. and Alitalo, K. Lymphangiogenesis: molecular mechanisms and futurepromise. Cell, 140: 460-76, 2010.Tvorogov D. Et al., Effective suppression of vascularnetwork formation by combination of antibodies blocking VEGFR ligand binding andreceptor dimerization. Cancer Cell, in press 2010.Plenary LecturesIlchun Plenary LectureGenetics of variation in human gene expressionVivian G. CheungHoward Hughes Medical Institute, Departments of Genetics & Pediatrics, University ofPennsylvania, USAGene expression underlies phenotypic and disease manifestations. To understand thepolymorphic regulation that affects gene expression in human cells, we use a combinationof genetic and molecular methods. In this presentation, I will describe results from geneticmapping studies where we treated expression levels of genes as quantitative traits andidentified polymorphic regulators that act in cis and in trans to affect gene expression.Results included over 1,000 trans-acting regulators that were not known to influencehuman gene expression at baseline. In addition, I will show that trans-acting regulatorssuch as kinases affect gene expression and cellular response to metabolic demands.Lastly, in the presentation, I will describe how advances in sequencing technology haveenabled our study of genome variation. Together, my presentation will illustrate thatstudies of genome variation provide a better understanding of gene regulation in humancells.2011년도 생화학분자생물학회 연례국제학술대회65