Role of wound provisional matrix in endothelial function

描述(由申请人提供)： 应聘者计划成为一名内科科学家，近期目标是通过严格的科学培训来补充他在整形外科的临床经验，长期目标是为我们的事业做出重大贡献。了解伤口修复过程中潜在的分子机制。为了实现这一点，提出了一个分两个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工作过渡到结合临床观点的独立研究。应聘者将通过以下提议的项目发展研究技能。 伤口修复始于纤维蛋白凝块，它充当临时细胞外基质(ECM)，招募伤口愈合所需的细胞。细胞外基质与细胞外基质的相互作用在创伤细胞功能中起着至关重要的作用。这项提案将考察它们对内皮细胞功能和毛细血管形成的贡献。纤维蛋白凝胶通常用于管状结构的研究。基于三维(3D)纤维蛋白凝胶并允许掺入纤维连接蛋白(FN)和其他ECM蛋白的伤口临时基质的体外模型将用于确定伤口基质的重要成分FN和Tenascin-C在控制内皮细胞重组为3D管结构中的作用。需要验证的假设是：1)纤维蛋白基质中FN的存在是毛细血管形态发生所必需的，2)Tenascin-C通过影响细胞-FN相互作用调节三维纤维蛋白-FN基质中毛细管网络的组装，以及3)FN和Tenascin-C调控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细胞外基质在内皮细胞功能中的作用及其在组织损伤反应中的作用。最终目标是为烧伤等损伤引起的疾病开发更有效的治疗策略。

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.