Project Summary Sepsis is a life-threatening condition of organ dysfunction caused by a deregulated host response to infection. Our research is focused on understanding the mechanisms of sepsis-induced cardiomyopathy, with an ultimate goal of developing new therapies. In our recently published study in Circulation (May, 2018), we obtained strong evidence showing that Beclin-1, a core regulator of autophagy, mitigates inflammation and improves cardiac function during endotoxemia. We hypothesize that Beclin-1 is a prospective new and key therapeutic target for sepsis-induced cardiac dysfunction. In this application, we will test this hypothesis using both genetic and pharmacological approaches in sepsis models in vitro and in vivo. We will determine the mechanisms of how Beclin-1 protects the heart by a regulatory pathway via mitochondria-associated membranes (aim 1) and by a selective induction of adaptive mitophagy (aim 2) during sepsis. We will further perform a comprehensive preclinical evaluation for a newly developed Beclin-1-activating peptide in clinically relevant models (aim 3). We expect that these investigations will not only advance the fundamental understanding of sepsis pathogenesis, but also identify a novel therapy with promising potential to improve patient care quality and clinical outcomes for sepsis.