Recent work has shown that integrins are important transducing receptors. Subsequent to integrin ligation and clustering, a number of distinct but inter-related signaling events have been demonstrated in various cell lines including: (a) activation of the cytoplasmic tyrosine kinase FAK and subsequent effects on cytoskeletal functions proteins; (b) activation of MAP kinases; (c) activation of transcription factors, including NF-kB, and consequent induction of several families of genes; (d) alterations in the expression and activity of components of the cell cycle machinery and subsequent effects on mitogenesis; (e) regulation of programmed cell death processes. These integrin-mediated events are likely to play an important role in regulating the growth and differentiation of many types of cells, including those of the vascular system. Many important issues regarding integrin signaling remain to be addressed. These include: (1) precise delineation and quantitation of the signaling pathways directly activated by integrins in various cell types; (2) elucidation of the mechanism(s) whereby integrin-mediated anchorage and soluble mitogens cooperate in signal transduction and in regulation of cell cycle traverse; (3) identification of genes that are strongly regulated by integrin signals and characterization of the mechanism of regulation; (4) evaluation of the role of integrins in apoptosis. This proposal seeks to address some of these key issues, working in several cellular model system that are relevant to vascular biology. Using fibroblasts as a tractable model system, we will seek to elucidate, in both qualitative and quantitative terms, how integrins and soluble mitogens collaborate in signal transduction cascades. We will also investigate the mechanistic basis of integrin-mitogen collaboration in cell cycle regulation. These activities will constitute a major thrust for this proposal. There is very little known about integrin signaling and integrin-modulated gene expression in vascular endothelial cells or in vascular smooth muscle cells. Since these cells play key roles in diseases of the vessel wall, it seems important to examine integrin signaling in this context. In endothelial cells, we will examine signaling processes activated by or modulated by integrins, using techniques we have previous developed for fibroblasts. We will also determine how integrins influence the expression of certain genes that are characteristically expressed in endothelial cells and that are vital for cell function. We will also explore aspects of anchorage control of apoptosis in these cells. In vascular smooth muscle cells we will examine signaling processes that regulated cell growth and cell hypertrophy and elucidate the impact of integrin engagement on these events.
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