Role of wound provisional matrix in endothelial function

描述（由申请人提供）： 候选人计划成为一名医生科学家，其近期目标是通过严格的科学培训来补充他在整形外科方面的临床经验，并为我们的长期目标做出重大贡献。理解伤口修复过程的分子机制。为了实现这一目标，提出了一个2阶段的职业发展计划，允许候选人在5年内从监督研究和课程过渡到纳入临床观点的独立调查。候选人将通过以下拟议项目发展研究技能。 伤口修复始于纤维蛋白凝块，其充当临时细胞外基质（ECM），其募集伤口愈合所需的细胞。细胞-ECM相互作用在伤口细胞功能中起关键作用。本研究将探讨它们对内皮细胞功能和毛细血管形成的作用。纤维蛋白凝胶通常用于试管形成研究。将使用基于三维（3D）纤维蛋白凝胶并允许并入纤连蛋白（FN）和其他ECM蛋白的伤口临时基质的体外模型来确定FN和腱生蛋白-C（伤口基质的重要组分）在控制内皮细胞重组成3D管结构中的作用。待测试的是以下假设：1）纤维蛋白基质中FN的存在对于毛细血管形态发生是必需的，2）腱生蛋白-C通过影响细胞-FN相互作用来调节3D纤维蛋白-FN基质中毛细血管网络的组装，以及3）由FN和腱生蛋白-C调节的血管形成在异常瘢痕形成中起重要作用。这些实验将有助于我们理解ECM在内皮细胞功能中的作用及其对组织损伤反应的贡献。最终的目标是开发更有效的治疗策略，用于由损伤如烧伤引起的病症。

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.