Summary For a complex organ like heart, well-organized interactions between different cell types are essential for its effective functioning. Cell-cell communication between these myriad cell types therefore appears to be key component of cardiac function and a better understanding of how different cells within injured myocardium communicate with each other during homeostasis and injury and elucidation of molecular events downstream of such communications is critical to identify new therapeutic targets for cardiac healing after injury. Increasing evidence suggest that extracellular vesicles (EVs) including exosomes are major paracrine conduits of cardiac cell-cell communication in homeostasis and disease conditions. However, a comprehensive understanding of how cardiac injury alters exosome-mediated cell-cell communications both locally within myocardium and at long distance organs such as bone marrow and adipose tissue and whether these exosome-mediated alterations in cell-cell communications influence overall cardiac structure and function and repair is not well understood. The overarching hypothesis of this renewal application is that cardiac injury alters exosome- mediated specific cell-cell communication both locally within the injured myocardium and distally with other organs and these intra-cellular and inter-organ communications influence overall myocardial responses to injury and repair processes. To test our hypothesis, we have assembled a team of highly accomplished scientists who have the potential to markedly advance the science and application of exosome biology for ischemic tissue repair. In particular, the design of this program, highlighted in inter-related yet unique individual projects, intends to capitalize on our existing synergy and assets. We will utilize the advantage of strategically designed scientific cores that will support each project. We will apply various techniques of molecular, cellular, and biochemical approaches in cell models and mice models of myocardial injury and repair. Project 1 (Kishore) examines the role of stressed cardiomyocyte-derived exosomes, particularly cardiomyocyte specific microRNAs, on post-injury endothelial and endothelial progenitor cell function and angiogenesis. Project 2 (Walter Koch) focuses upon the involvement of cardiac exosomes containing G-protein coupled receptor kinase 2 on adipocytes and cardiac cell function. Project 3 (Tilley) examines the role of beta-2 adrenergic receptor on myeloid cell exosomes and cardiac functions. All three projects involve in-depth molecular, cellular, and physiological studies comprising of mouse models of myocardial injury. Establishing the role of exosomes in post-injury cell to cell communications may identify new mechanisms and therapeutic targets for post-injury myocardial repair. The goal of this program will be to delineate exosome mediated signaling mechanisms and determine how they can be utilized to restore and enhance endogenous cellular r...