Cardiomyocyte Integrin-Matrix Interactions Regulate Cardiac Fibrosis



 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.