This application is for competitive renewal of the Program Project """"""""Mechanisms of Acute Vascular Reaction to Injury"""""""". This long-standing program has made seminal contributions to our understanding of the origins of the arterial intima and the formation of atherosclerotic lesions in the intima. Critical contributions in the past include demonstrations of monoclonality, development of the standard """"""""three wave"""""""" model for formation of an intima after angioplasty, cloning of intimal-specific genes, and identification of growth factors required for formation of the intima. These interests continue to be pursued in the renewal. Two projects (Projects 1 and 2) focus on mechanisms of apoptosis in endothelial and smooth muscle cells, including the pro-apoptotic caspase pathway and anti-apoptotic pathways mediated by bcl-2 homologues. The focus in Project 1 is on model systems designed to explore the role of apoptosis in the failure of vessels to accommodate growth of atherosclerotic plaque. Project 2 focuses on apoptotic resistance, primarily in endothelial cells, mediated by cytokines that can protect as well as kill. Project 6 uses innovative chimeric animals and a genetically engineered intima to study, for the first time, the role of endogenous growth factors. The same technology is used in several of the other projects, especially to address issues of the biology of pre-existing intima. We know how an intima is formed, but pathologic responses occur in a pre-existing intima. In Project 4, the critical issue is understanding the response to growth factors once an intima is already formed. Project 5 also looks at the intima, studying the role of integrins in forming the intima and role of an intimal-specific gene, osteopontin in determining intimal function. Finally, our knowledge of how the intima is formed has begin to be useful to another area developed during our last funding period--the repair of injured myocardium. Our previous Project 3 explored cardiac cell differentiation. Project 3 in this competitive renewal uses that information as well as tools from our work on the formation of intima, especially genetically engineered cells, to attempt to recreate sarcomeric muscle in the myocardium. These six projects are supported by a Core that assists in analysis of tissue and development of animal models, and by an Administrative Core.
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