Molecular Engineering of Damaged Myocardium To Enhance Regeneration And Repair

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DESCRIPTION (provided by applicant): Discovery of cardiac progenitor cells (CPCs) in the adult heart has led to heightened expectations for novel treatments of cardiac disease. However, adoptive transfer of CPCs results only in transient improvement of cardiac performance because most of the donated cells fail to persist in the hostile milieu of the ischemic scar. Whereas most approaches focus upon enhancing capabilities of stem cells, engineering of the damaged myocardium is a valid alternative strategy to enhance myocardial repair and regeneration. Extracellular matrix (ECM) proteins are pivotal components of the myocardial environment important in maintenance of cellular function. Therefore, the overall goal of this proposal is to improve the survival, proliferation, recruitment, and persistence of CPC in the damaged myocardium by modification of fibronectin (Fn) expression, an ECM protein which correlates highly with spatio-temporal appearance of CPCs in the heart. Our preliminary data delineate a Fn-?5?1-FAK-Pim-1 signaling cascade that regulates CPC growth and survival. The relevance of Fn, ?5?1, FAK and Pim-1 in cardiomyocyte biology are well accepted, however, nothing is known so far about this pathway in CPCs. Therefore, the short term goal is to understand the significance of the Fn-?5? 1-FAK-Pim-1 pathway in CPCs under pathological conditions and extrapolate an innovative therapeutic approach to engineer the extracellular environment of the damaged myocardium to enhance regeneration and repair. Translational potential of these findings will be explored using an adeno-associated virus type 9 (AAV9) vector to express a functional collagen-tethered Fn fragment designed to enhance CPC survival, proliferation, recruitment, and engraftment. Our specific aims are: 1) The Fn-?5?1-FAK-Pim-1 signaling axis is triggered following cardiomyopathic injury in vivo, 2) ?5?1-integrin receptor activation by Fn induces immediate early stress responses, survival, and proliferation via FAK-Pim-1 signaling in CPCs, 3) Robust and persistent CPC- dependent regeneration is mediated by overexpression of a collagen binding Fn fragment delivered by cardiotropic AAV9 vector. The significance of these studies is to define beneficial aspects of the endogenous repair to injury response. The long term goal will be to transfer the Fn fragment expressing AAV9 regimen into human disease establishing an innovative therapeutic concept for regenerative medicine. PUBLIC HEALTH RELEVANCE: Heart disease, especially heart failure is a major public health issue in the United States with a considerable burden for the health care system. Despite recent progress in understanding the pathophysiology, heart failure still carries a 5-year mortality that rivals most cancers. This proposal focuses upon understanding how the environment of the damaged heart can impact upon repair and regeneration on a cellular and molecular level. Defining these issues on a mechanistic level will lead to novel approaches to enhance treatment of heart disease and aging.