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Dean Sheppard received an AB (Social Studies) from Harvard College in 1972, and an MD from SUNY at Stony Brook in 1975. He trained in Internal Medicine at the University of Washington in Seattle and in Pulmonary Medicine at UCSF. He has been on the faculty in the Department of Medicine at the San Francisco General Hospital campus of UCSF since 1980 and was appointed the founding director of the Lung Biology Research Center in 1986. Currently, he is a Professor of Medicine, a member of the Cell Biology, Biomedical Sciences and Pharmaceutical Sciences and Pharmacogenomics graduate programs, and serves as the Associate Chair for Biomedical Research in the Department of Medicine and as the Associate Director of the Sandler Center for Basic Research in Asthma.
Dr. Sheppard’s research focuses on how cells use members of the integrin family to detect, modify and respond to spatially restricted extracellular clues. Much of the work is focused on four members of this family, the epithelial-restricted integrin, avb6, and the widely expressed integrins a9b1, avb5 and avb8. avb6 has two distinct functions: enhancement of cell proliferation, and activation of latent transforming growth factor beta (TGFb), that depend on distinct sequences in the b6 cytoplasmic domain. We have shown that the latter function plays a central role in tissue fibrosis, acute lung injury, protection from pulmonary emphysema, tumor invasion and in the airway hyperresponsiveness that follows chronic allergen challenge. Currently we are identifying pathways that regulate each of these responses. We have also identified several components of the signaling pathways by which cells regulate integrin-dependent TGFb activation and are currently determining the injury-related stimuli that activate these pathways. The avb8 integrin also activates TGFb. Mice we have generated lacking this integrin on dendritic cells develop auto-immunity and colitis, suggesting avb8-mediated TGFb activation on dendritic cells negatively regulates adaptive immunity. We are currently characterizing the mechanisms underlying this effect, the mechanisms by which this process is regulated during the induction of adaptive immune responses, and the relevance of this pathway in various models of immune-mediated disease.
a9b1 is expressed by a wide variety of cells and recognizes at least 15 distinct ligands. a9b1 is critical for cell migration, an effect that depends on unique sequences in the a9 cytoplasmic domain. We are identifying and characterizing proteins that specifically bind to these sequences and the downstream signals that mediate enhanced migration. As a9 ko mice are not viable, we have generated mice expressing a conditional null allele to better the role of this integrin in vivo. a9 knockout mice die from a defect in lymphatic development, and we are currently working to identify the molecular mechanisms by which this integrin contributes to lymphangiogenesis and angiogenesis.
avb5 is also widely expressed, but mice lacking this integrin are phenotypically normal. However, these mice are dramatically protected in multiple models of acute lung injury. This phenotype is explained, at least in part, by a central role for this integrin in regulating reorganization of the actin cytoskeleton in activated endothelial cells. We are currently examining the mechanisms by which this integrin, and its close relative, avb3, exert opposing effects on actin organization, vascular permeability and tissue edema.
Current treatments of most common lung diseases are ineffective or toxic, in part due to limited understanding of the molecular events underlying these diseases. We are taking an unbiased approach to this problem, combining global analysis of gene expression and computational analysis of genetic loci responsible for differences in disease models in inbred strains of mice. In parallel, we are generating mice expressing null mutations of leading candidate genes identified from our screening approaches. To complement this strategy, we are part of a Bay area consortium Baygenomics that is generating a library of mouse embryonic stem cells containing inactivating mutations in random murine genes and generating selected lines of mice expressing null mutations of genes predicted to contribute to lung development or disease. Thus far, we have targeted more than 3000 individual genes and are beginning to evaluate selected lines for abnormalities in lung development and in models of acute lung injury, asthma and pulmonary fibrosis.
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 αvβ6 binds and activates latent TGFβ: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 1999, 96: 319-328.
Kaminiski 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 fibrosis reveals distinct programs regulating lung inflammation and remodeling. Proc Nat Acad Sci 2000 97:1778-1783.
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 of acute lung injury. J. Clin. Invest. 2001 107:1529-1536.
Morris DG, Huang X, Kaminski N, Wang Y, Shapiro SD, Dolganov G, Glick, A, Sheppard D. Loss of integrin αvβ6-mediated TGFβ activation causes Mmp12-dependent emphysema. Nature 2003 422:169-173.
Chen C, Young BA, Coleman CS, Pegg AE, Sheppard D. Spermidine/Spermine N1-Acetyltransferase specifically binds to the integrin α9 subunit cytoplasmic domain and enhances cell migration J Cell Biol 2004 167:161-170.
Vlahakis NE, Young BA, Atakilit A, Sheppard D. The lymphangiogenic growth factors VEGF-C and D are ligands for the integrin α9β1. J Biol Chem 2005 280:4544-52.
Jenkins RG, Su X, Su G, Scotton, CJ, Camerer E, Laurent GJ, Davis JE, Chambers RC, Matthay MA, Sheppard D. Ligation of the protease-activated receptor-1 induces avb6 integrin-dependent TGFb activation and promotes acute lung injury. J Clin Invest 2006 116:1606-1614.
Chen C, Huang X, Atakilit A, Zhu Q-S, Corey SJ, Sheppard D. The integrina9b1contributes to granulopoiesis by enhancing granulocyte colony stimulating factor receptor signaling. Immunity 2006 25:895-906.
Vlahakis NE, Young BA, Atakilit A, Hawkridge AE, Isaaka RB, Boudreau N, Sheppard D. Integrina9b1directly binds to vascular endothelial growth factor (VEGF)-A and is necessary for VEGF-A and tumor-induced angiogenesis. J Biol Chem 2007 282:15187-96.
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 integrinavb8on dendritic cells causes autoimmunity and colitis in mice. Nature 2007 449:361-365.
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