Cell-extracellular matrix interactions are tightly regulated by """"""""inside-out"""""""" signals that activate integrins. Integrin ligation and clustering localize and activate proteins at cell adhesion sites to initiate """"""""outside-in"""""""" signals that mediate biological responses. No where is this bidirectional signaling more apparent than in blood and vascular cells, where integrins control growth, differentiation, survival and function. The purpose of this Program Project is to characterize fundamental mechanisms of integrin signaling in blood and vascular cells. Individual projects will examine platelets, endothelial cells and smooth muscle cells, but the common goal is to identify general rules of integrin signaling. Project 1 will test the hypothesis that outside-in signaling in platelets is triggered by dynamic and direct interactions between integrins, Src family kinases and Src regulatory proteins. Molecular mechanisms of this process will be characterized, and consequences of disrupting these interactions on thrombus formation will be determined in gene-targeted mice. Project 2 has characterized the roles of ERK 1/2, Rap1, R-Ras and PEA-15 in integrin activation. It will now test the hypothesis that specific effectors of Rap1 and R-Ras mediate this process, in part through interactions with talin. Since PEA-15 is expressed in vascular cells, its roles in vessel repair and angiogenesis will be determined. Project 3 will characterize how integrin ligation influences endothelial cell barrier disruption induced by VEGF during ischemic disease and how basement membrane proteins exposed during vascular leak recruit platelets to form deleterious micro-thrombi. It will also characterize how semaphorin-3A promotes vascular leak in the absence of VEGF and inhibits angiogenesis. Project 4 will examine relationships between the Abl tyrosine kinase and integrin signaling. It will test the hypotheses that beta3 integrin activates Abl through Src-dependent tyrosine phosphorylation of p62Dok-1, and that Abl phosphorylates Src-substrates to inhibit cell spreading. The relationships between Abl and known regulators of F-actin will be determined by identification of genes that modulate Abl function using an shRNA library screen. These projects will be supported by core units that provide recombinant proteins, cell imaging capabilities and administrative coordination. The synergy achieved by this Program will further our understanding of integrin signaling, with implications for disorders of cell adhesion affecting hemostasis and vascular repair.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Kindzelski, Andrei L
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University of California San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
United States
Zip Code
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