Dean Sheppard, M.D.
Professor and Associate Chair for Biomedical Research
Director of the Lung Biology Center
Associate Director, Sandler Asthma Basic Research Center
University of California, San Francisco
Mission Bay Rock Hall 1550-4th Street
Room 548E,Box 2922
San Francisco, CA 94158
Tel: (415) 514-4269
Fax: (415) 514-4278
Dean Sheppard, Associate Director of the Sandler Asthma Basic Research in Center, 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.
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,αvβ6, and the widely expressed integrins α9β1 and αvβ5. αvβ6 has two distinct functions: enhancement of cell proliferation, and activation of latent transforming growth factor beta (TGFβ), that depend on distinct sequences in the β6 cytoplasmic domain. Currently we are identifying pathways that regulate each of these responses and are using tissue specific rescue transgenes in β6 ko mice to characterize the roles of these pathways in vivo. We have also identified several components of the signaling pathways by which cells regulate integrin-dependent TGFβ activation and are currently determining the injury-related stimuli that activate these pathways.
α9β1 is expressed by a wide variety of cells and recognizes at least 15 distinct ligands. α9β1 is critical for cell migration, an effect that depends on unique sequences in the α9 cytoplasmic domain. We are identifying and characterizing proteins that specifically bind to these sequences and the downstream signals that mediate enhanced migration. As α9 ko mice are not viable, we are generating mice expressing a conditional null allele to better the role of this integrin in vivo. α9 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. We have also identified two other unique roles of α9β1 in enhancement of the rate of cell migration and in the development of granulocytes and are in the process of characterizing the molecular mechanisms underlying each function. αvβ5 is also widely expressed, but mice lacking this integrin are phenotypically normal. However, these mice have a specific defect in regulation of vascular permeability. This function plays a central role in several models of pulmonary edema, and appears to be explained by a role for αvβ5 in regulating the function of the endothelial cell-cell adhesion protein VE-Cadherin. We are currently characterizing the signaling pathways responsible for this effect.
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.