The primary goal of this proposal is to train the principal investigator to become an independent laboratory based investigator in the field of cardiac failure. To accomplish this goal, the principal investigator proposes a detailed training program in the investigation of the mechanisms of cardiac fibrosis in a transgenic mouse model. Several key collaborators will assist in this goal. They include her sponsor, Dr. David Dichek, an expert in gene manipulation in animal models of cardiovascular disease. Dr. Charles Murry, Pathology, will assist in the analysis of myocardial histology. In addition, the principal investigator presents a training plan including specific coursework, conferences, and the formation of an advisory committee to guide her development as a physician-scientist. Cardiac fibrosis is a common finding in end-stage heart failure independent of etiology. Mechanisms leading to the development of cardiac fibrosis are poorly defined. Recent work in the Dichek lab has indicated a possible role for urokinase plasminogen activator(uPA) in cardiac fibrosis. To define mechanisms involved in the development of cardiac fibrosis, the candidate proposes the following specific aims. 1)To test the hypothesis that cardiac fibrosis is mediated by increased activation of latent transforming growth factor-beta 1 (TGF-beta1) leading to increased fibroblast activation. 2) To determine the role of plasminogen, matrix metalloproteinases and the uPA receptor in cardiac fibrosis. 3) To test the hypothesis that altered gene expression by bone marrow derived cells is sufficient to modulate cardiac fibrosis. The University of Washington has outstanding resources for the development of physician-scientists in cardiovascular diseases. There exists a strong collaborative approach to the study of cardiovascular biology between various departments and core laboratories. This environment will allow the principal investigator to gain both the technical expertise and the critical thinking skills necessary to develop into an independent investigator in cardiac failure.
