PROJECT SUMMARY/ABSTRACT Groundbreaking discoveries resulting in the “immuno-revolution” have established the importance of immunology across medical disciplines. Inflammation has long been considered as an important mechanism contributing to the progression of ischemic and nonischemic forms of heart failure. Countless studies have reported associations between numerous serum cytokines, adverse left ventricular remodeling, and patient outcomes in the settings of chronic heart failure and myocardial infarction. While these observations highlight the potential utility of suppressing inflammation in the heart, early clinical studies investigating anti- inflammatory therapies in patients who experienced a myocardial infarction (corticosteroids) or those with chronic heart failure (corticosteroids, TNF blockade) revealed disappointing results and dampened enthusiasm around further drug development. At that time, limited information existed regarding the precise immune cell types that promote disease and the signaling mechanisms that exert their effects. In recent years, a renewed interest in targeting the immune system in cardiovascular disease has emerged. This resurgence is powered by the discovery of the cellular mediators of inflammation in the heart and the identification of the mechanisms that orchestrate their activation and damaging effector functions. These findings exemplify the exciting, but unmet, opportunity to effectively target the immune system and improve outcomes for individuals with cardiac diseases. The proposed research program will built upon our laboratory’s prior accomplishments that have uncovered remarkable diversity amongst the composition and function of macrophages in the healthy, failing, and transplanted heart. We will integrate 3 active projects into a unified research program that aims to 1) dissect new biological mechanisms governing cardiac macrophage diversity and function, and 2) translate our findings into new diagnostic and therapeutic approaches to abrogate heart failure pathogenesis, potentiate functional recovery of the failing heart, and prevent heart transplant rejection. Key themes will include the roles of mechanosensing, inflammatory signaling, and monocyte fate specification in the pathogenesis of heart failure across disease etiologies, cardiac tissue repair and recovery, and heart transplant rejection.