This is a competitive renewal of a program project that has been committed to studies of the basic biology of vascular responses to injury. Over the years the focus of the grant has moved from mechanisms of vascular inflammation to mechanisms of cell injury and cell proliferation. The current version includes ten projects and four cores. Four projects are directed at studying the mechanisms of smooth muscle cell proliferation, including an attempt to identify genes responsible for control of smooth muscle proliferation, studies of control of smooth muscle proliferation in cell culture, animal models of smooth muscle proliferation in the absence of denuding injury, and identification of the range of mitogens likely to be delivered to a vessel wall by inflammatory cells. The next four projects deal with developmental biology and cell injury in vessel wall cells, with an emphasis on the endothelium. These include studies of the in synthesis by endothelial cells in response to various kinds of injuries, effects of inflammatory mediators on endothelium, production of pro- and anti-coagulants by endothelial cells, and interactions of endothelial cells mediated by intercellular adhesive molecules. The two final projects may be viewed as applications of this more basic material to problems of clinical significance. This includes one project directed at understanding smooth muscle function in the normal and hypertensive animal and one project devoted to the study of the evolving atherosclerotic lesion. Both of these projects have been designed to make use of information gathered from the more basic studies. Finally, the Core laboratories include facilities for cell culture, image analysis, and morphology.
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