Role of wound provisional matrix in endothelial function

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DESCRIPTION (provided by applicant): The candidate plans to be a physician-scientist with the immediate goal of complementing his clinical experience in plastic surgery with rigorous scientific training and the long-term goal of making significant contributions to our. understanding of molecular mechanisms underlying the wound repair process. To achieve this, a 2-phase career development plan is proposed which allows the candidate to transition over a 5-year period from supervised research and coursework to independent investigations incorporating clinical perspectives. The candidate will develop research skills through the following proposed project. Wound repair begins with the fibrin clot, which acts as a provisional extracellular matrix (ECM) that recruits necessary cells for wound healing. CelI-ECM interactions play a critical role in wound cell function. This proposal will examine their contributions to endothelial cell function and capillary formation. Fibrin gels are routinely used in tube formation studies. An in vitro model of the wound provisional matrix based on a three-dimensional (3D) fibrin gel and allowing incorporation of fibronectin (FN) and other ECM proteins will be used to determine the roles of FN and tenascin-C, important components of the wound matrix, in controlling endothelial cell reorganization into 3D tube structures. To be tested are the following hypotheses: 1) the presence of FN in fibrin matrices is essential for capillary tube morphogenesis, 2) tenascin-C modulates the assembly of capillary tube networks in 3D fibrin-FN matrices by affecting celI-FN interactions, and 3) blood vessel formation modulated by FN and tenascin-C plays a significant role in abnormal scar formation. These experiments will contribute to our understanding of the role of the ECM in endothelial cell function and their contributions to the tissue response to injury. An ultimate goal is the development of more effective therapeutic strategies for conditions resulting from injury such as burns.