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,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.
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 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 a9ß1 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.
Mice homoygous for a non-conditional null allele of β8 die before or soon after birth so we have also been utilizing mice expression a conditional null allele of the β8 subunit to examine the roles of this integrin in lung development and immune homeostasis. These studies have demonstrated critical roles for β8 on lung epithelial cells in normal lung development and a critical role for β8 on dendritic cells for regulation of cognate immune responses and prevention of auto-immunity. We are currently identifying the molecular pathways underlying these responses and beginning to determine the relevance of this effect on cognate immune to models of various diseases characterized by abnormal immune responses.
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.
The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis.
[Cell. 1999 Feb 5;96(3):319-28.]
Munger JS, Huang XZ , Kawakatsu H , Griffiths MJD, Dalton SL, Wu JF, Pittet JF, Kaminiski N, Garat C, Matthay MA, Rifkin DB, Sheppard D.
Fatal bilateral chylothorax in mice lacking the integrin alpha9beta1.
[Mol Cell Biol 2000 20:5208-15.]
Huang XZ, Wu JF, Ferrando R, Lee JH, Wang YL, Farese RV Jr, Sheppard D.
TGFβ is a critical mediator of acute lung injury.
[J Clin Invest. 2001 Jun;107(12):1537-44.]
Pittet J-F, Griffiths MJD, Geiser T, Kaminski N, Dalton SL, Huang X, Brown LAS, Gotwals PJ, Koetiansky VE, Matthay MA, Sheppard D.
Src-mediated coupling of focal adhesion kinase to integrin alpha(v)beta5 in vascular endothelial growth factor signaling.
[J. Cell Biol. 2002; 157:149-160.]
Elicieri BP, Puente XS, Hood JD, Huang X, Schlaepfer DA, Sheppard D, Cheresh DA.
Loss of integrin αvβ6-mediated TGFβ activation causes Mmp12-dependent emphysema.
[Nature 2003 422:169-173.]
Morris DG, Huang X, Kaminski N, Wang Y, Shapiro SD, Dolganov G, Glick, A, 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.]
Chen C, Young BA, Coleman CS, Pegg AE, Sheppard D.
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 αvβ6 integrin-dependent TGFβ activation and promotes acute lung injury. J Clin Invest 2006 116:1606-14
Chen C, Huang X, Atakilit A, Zhu Q-S, Corey SJ, Sheppard D. The integrin α9β1 contributes to granulopoiesis by enhancing granulocyte colony stimulating factor receptor signaling. Immunity 2006 (in press)