Heart failure progression is a complex biological process that is precipitated by the maladaptive myocardial response to injury, compounded by failure of the adult heart to replace lost or damaged cardiomyocytes. Conceivably, identifying common pathways that regulate these two seemingly unrelated processes would profoundly impact therapeutic strategies to prevent, and even reverse heart failure progression. Numerous observations by members of the proposed consortium and others support the notion that the endogenous capacity of the neonatal mammalian heart to proliferate fades in the early postnatal life as a switch from hyperplastic to hypertrophic growth of cardiomyocytes takes place. Members of the proposed consortium and others have also previously demonstrated that mechanisms linked to activation of immune response may play a role in cardiomyocyte hypertrophy, death, healing and even stimulation of new cardiomyocyte generation. The current proposal brings together several groups with significant expertise in immunology, myocardial remodeling, hypertrophy and regeneration with the overall goal of determining the role of immune response signaling in regulation of cardiac growth, healing and regeneration. Indeed, the immune response has taken center stage in the past several years as a primary determinant of both healthy cardiac aging and healing after injury, as well as a determinant of chronic disease states when it is inappropriately regulated. Thus, this Program Project will investigate a frontier and emerging area of scientific investigation involving the intersection between the immune system and the myocardium. Specifically, studies will examine the role of innate immune response signals in cardiomyocyte cell cycle regulation, as well as in myocardial remodeling and hypertrophy. In addition, dedicated studies will examine the role of cGAS-STING expression in cardiomyocytes and in immune cells in regulation of cardiac growth and regeneration. Finally, studies in the proposed Program Project will examine the role of macrophage subtypes in mediating myocardial response to cell therapy as well as injury. The proposed Program Project is well in line with the interest and expertise of the groups in the network and extends their focus into a highly relevant and poorly explored area of cardiac pathophysiology. The current proposal creates a new shared focus for all the groups in the Program Project that aims to establish a new paradigm in the field.