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Molecular
Mechanisms of Asthma, Pulmonary Fibrosis and Acute L ung
Injury and Functions of Integrins in Cells and Mammals
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 two members of this family, the epithelial-restricted
integrin avb6, and the widely expressed integrin a9b1. avb6 has two distinct
functions: enhancement of cell proliferation, and activation of latent
transforming growth factor beta (TGFbeta), that depend on distinct sequences
in the b6 cytoplasmic domaint. 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.
a9b1 is expressed by a wide variety of cells and recognizes at least 15
distinct ligands. a9b1is 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 are generating mice expressing a conditional null allele
to better the role of this integrin in vivo.
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.
Selected Publications:
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
avb6 binds and activates latent TGFb1: a mechanism for regulating pulmonary
inflammation and fibrosis. Cell 1999, 96: 319-328.
Taooka Y, Chen J, Yednock T, Sheppard D. The integrin a9b1 mediates adhesion
to activated endothelial cells and trans-endothelial neutrophil migration
through interaction with vascular cell adhesion molecule 1. J. Cell Biol
1999, 145:413-420.
Kaminski 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. TGFbeta is a critical
mediator of acute lung injury. J. Clin. Invest. 2001 107:1529-1536.
Young BA, Taooka Y, Liu S, Askins J, Yokosaki Y, Thomas SM, Sheppard D.
The cytoplasmic domain of the integrin alpha9 subunit requires the adaptor
protein paxillin to inhibit cell spreading but promotes cell migration
in a paxillin-independent manner. Mol Biol Cell 2001 12:3214-3225.
Contact Information:
Email: deans@itsa.ucsf.edu
Phone: 415/ 514-4269
Address: Box 2922, 1550 4th Street, Room 548 E
The University of California, San Francisco, CA 94143, (415) 476-9000
Copyright 2003, The Regents of the University of California.
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