Cardiomyocyte Integrin-Matrix Interactions Regulate Cardiac Fibrosis

 描述(由申请者提供)：NRSA个人博士后奖学金的目标是帮助Flevaris博士成为心血管医学领域的内科科学家和心脏纤维化研究的领导者。他和他的导师沃恩博士制定了一个多方面的培训计划，以加强他在医学和心脏病学方面的临床背景，并加强他的科学研究能力。在此授奖期间，Flevaris博士建议通过1)旨在提高他对基础科学研究方法的理解的课程工作，2)与临床医生和其他教员的合作，3)其他体内和体外方法的培训，以研究心脏病的机制，以及4)监督研究项目，从而培养更多的技能。每一次重要的经历都将帮助他过渡到独立调查员的职业生涯。本项目的总体科学目标是通过三个主要的特定目标来研究心肌细胞整合素-基质相互作用在心脏纤维化发展中的作用：1)在野生型小鼠和表现出年龄依赖性自发性心肌纤维化的小鼠中建立损伤介导的心脏纤维化模型；2)确定细胞外基质(ECM)的解离和心肌细胞整合素的组成对心肌纤维化的影响；以及3)确定特定的ECM蛋白对体外培养的心肌细胞整合素表达和信号转导的影响。该项目将在基础科学研究战略和写作方面提供正式的学术培训，以及有重点的指导计划，并将支持Flevaris博士向熟练的临床和基础科学家的纵向发展。这个项目 将履行国家卫生研究所的使命，支持与心脏纤维化基本机制相关的基本发现，最终目标是提供新的治疗目标和方法，以减少心血管疾病对公众健康的重大负担。从这个项目中获得的知识将直接提高我们对心脏纤维化患者发生、发展和临床结果的潜在机制的理解。Flevaris博士计划利用该项目的结果提交临床研究人员奖申请或类似的拨款，进一步研究心血管疾病的分子机制。

 DESCRIPTION (provided by applicant): The goal of this NRSA individual postdoctoral fellowship is to assist the development of Dr. Flevaris as a physician scientist in the field of cardiovascular medicine, and a leader in cardiac fibrosis research. He and his mentor, Dr. Vaughan, have developed a multifaceted training plan in order to build upon his clinical background in medicine and cardiology, and strengthen his scientific investigational abilities. During this award period, Dr. Flevaris proposes to develop additional skills through 1) coursework designed to improve his understanding of basic science research methodologies, 2) collaboration with clinicians and other faculty, 3) training in additional in vivo and in vitro approaches to study the mechanisms of cardiac disease, and 4) a supervised research project. Each of these vital experiences will help support his transition to a career as an independent investigator. The overall scientific objective of this project is to investigate the role of cardiomyocyte integrin-matrix interactions in the development of cardiac fibrosis through three primary specific aims: 1) To perform an injury-mediated cardiac fibrosis model in wild type mice and in mice that demonstrate age-dependent spontaneous cardiac fibrosis; 2) To determine the effect of extracellular matrix (ECM) disorganization and cardiomyocyte integrin composition on cardiac fibrosis; and 3) To define the effect of specific ECM proteins on cardiomyocyte integrin expression and signaling in vitro. This project will provide formal academic training in basic science research strategy and writing, as well as a focused mentorship plan, and will support Dr. Flevaris' longitudinal development into a proficient clinical and basic scientist. This project will meet the mission of the National Institute of Health by supporting basic discoveries related to the fundamental mechanisms of cardiac fibrosis, with the ultimate goal of providing novel therapeutic targets and approaches to reduce the significant public health burden of cardiovascular disease. The knowledge gained from this project will directly improve our understanding of the mechanisms underlying the development, progression, and clinical outcomes of patients with cardiac fibrosis. Dr. Flevaris plans to submit a Clinical Investigator Award application or similar grant using the results of this project, further investigating the molecular mechanisms of cardiovascular disease.