Dean Sheppard, MD
|School||UCSF School of Medicine|
|Address||1550 4th St., Mission Bay|
School or Department
|University of California, San Francisco||Residency ||School of Medicine|
|SUNY, Stony Brook||M.D.||School of Medicine||1975|
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 of UCSF since 1980 and was appointed the founding director of the Lung Biology Research Center in 1986. He has been the Chief of the Division of Pulmonary, Critical Care, Allergy and Sleep since 2009. Dr. Sheppard is Professor of Medicine and a member of the Cell Biology, Biomedical Sciences, Immunology and Pharmaceutical Sciences and Pharmacogenomics graduate programs.
Dr. Sheppard’s research focuses on the molecular mechanisms underlying pulmonary (and other organ) fibrosis, asthma and acute lung injury. One aim of the research is to identify new therapeutic targets to ultimately improve the treatment of each of these common diseases. The work begins with basic investigation of how cells use members of the integrin family to detect, modify and respond to spatially restricted extracellular clues and how these responses contribute to the development of common lung diseases. Utilizing mice with global or conditional knockouts of four integrins, the epithelial-restricted integrin, avß6, and the widely expressed integrins a9ß1, avß5 and avß8, the lab has identified important roles for these integrins in models of each common lung disease and key steps upstream and downstream of the integrins that provide potential therapeutic targets.
avß6 has two distinct functions: enhancement of cell proliferation, and activation of latent transforming growth factor beta (TGFß), that depend on distinct sequences in the ß6 cytoplasmic domain. We have shown that the latter function plays a central role in pulmonary and renal 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. A humanized monoclonal antibody generated by immunizing our knockout mice is currently in clinical trials for treatment of pulmonary and renal fibrosis. We have also found that mice lacking all av integrins on myofibroblasts are protected from pulmonary, hepatic and renal fibrosis and are using this model to develop new approaches for treating a wide variety of fibrotic diseases.
The avß8 integrin also activates TGFß. Mice we have generated lacking this integrin on dendritic cells develop auto-immunity and colitis, suggesting avß8-mediated TGFß activation on dendritic cells negatively regulates adaptive immunity. However, these mice are dramatically protected from pathology in a number of immune-mediated disease models, including a model of allergic asthma. We are currently characterizing the mechanisms underlying these effects, 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.
a9ß1 is expressed by a wide variety of cells and recognizes at least 15 distinct ligands. a9ß1 is critical for cell migration, an effect that depends on unique sequences in the a9 cytoplasmic domain. 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. Mice lacking this integrin in airway smooth muscle cells develop spontaneous airway hyperresponsiveness, resembling asthma. We have used these mice and cells and tissues from their lungs to identify a completely novel pathway regulating airway smooth muscle contraction, and are currently working to develop specific inhibitors of pathway components in the hope of finding new treatments for asthma.
avß5 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 and septic shock. 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, avß3, exert opposing effects on actin organization, vascular permeability and tissue edema. We have also generated a potent blocking antibody to avß5 that we hope to develop for treatment of acute lung injury and septic shock.
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