My lab 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 three members of this family, the epithelial-restricted integrin avb6, and the widely expressed integrins a9b1 and avb5. avb6 has two distinct functions: enhancement of cell proliferation, and activation of latent transforming growth factor beta (TGF-b), that depend on distinct sequences in the b6 cytoplasmic domain. We have used b6 knockout mice to demonstrate important roles for these pathways in models of a number of common lung diseases, including acute lung injury, pulmonary fibrosis and emphysema. Currently we are identifying pathways that regulate each of these responses and are using tissue specific rescue transgenes in b6 ko mice to characterize the roles of these pathways in vivo.
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Selected Publications
Munger JS, Huang XZ , Kawakatsu H , Griffiths MJD, Dalton SL, Wu JF, Pittet JF, Kaminiski N, Garat C, Matthay MA, Rifkin DB and Sheppard D. (1999). The integrin avb6 binds and activates latent TGFb1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 96:319-328.
Pittet J-F, Griffiths MJD, Geiser T, Kaminski N, Dalton SL, Huang X, Brown LAS, Gotwals PJ, Koetiansky VE, Matthay MA and Sheppard D. (2001). TGFb is a critical mediator of acute lung injury. J Clin Invest 107:1529-1536.
Morris DG, Huang X, Kaminski N, Wang Y, Shapiro SD, Dolganov G, Glick, A and Sheppard D. (2003). Loss of integrin avb6-mediated TGFb activation causes Mmp12-dependent emphysema. Nature 422:169-173.
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