MECHANISMS OF CARDIOVASCULAR REACTION TO INJURY

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DESCRIPTION (provided by applicant): This application represents a competing renewal of the Program Project "Mechanisms of Cardiovascular Reaction to Injury". Now in its 48th year, this Program has made important contributions to our understanding of development of the vascular intima and the atherosclerotic plaque, including generating the "Response to Injury" and the "Monoclonal" hypotheses for the pathogenesis of atherosclerosis. The current application includes a new emphasis on the heart's response to injury, while continuing work in vascular biology as well. A central theme is that these two different types of muscle tissue will show many similarities in their reactions to injury. Our aims are to understand pathways to cell death, define normal adaptive and reparative responses of the injured tissues, and to develop molecular strategies to control these processes. Project 1 will focus on controlling proliferation of skeletal muscle cells after grafting into the infarcted heart, and defining the key molecules and cell differentiation pathways that regulate infarct repair. Project 2 will determine the extent to which cells in wound repair are derived from preexisting local sources, the bone marrow, or transdifferentiation of non-marrow cells. This project will also continue its studies of the role of the PDGF system in wound healing. Project 3 builds on the observation that arteries express many-fold higher levels of RGS proteins that do veins, testing the hypothesis that RGS proteins are critical mediators of vascular hypertrophy in hypertensive remodeling and formation of collateral circulation. These 3 projects are supported by an Animal/Tissue Core to assist in mouse husbandry and histology and by an Administrative Core. We expect that information from these studies will teach us, not only how to better grow new muscle in the injured heart, but also how to create a better "soil" in which new muscle can be grown.