Project Summary: Macro-autophagy and mitophagy (a mitochondria-specific form of autophagy) are constitutively active in the heart and essential to maintaining cardiomyocyte survival under stress by removing potentially harmful proteins and organelles. Extensive studies suggested the occurrence of macro-autophagy and mitophagy impairment early in the pathogenesis of heart failure (HF), but its precise role in HF progression is unclear, and the mechanism(s) of its origin remained elusive. We reported that the Sigma 1 receptor (Sigmar1) is a widely expressed protein in the heart. We have reported that Sigmar1 possesses a physiological role in maintaining healthy heart function, and Sigmar1 ablation results in cardiac contractile dysfunction. However, a myriad of Sigmar1’s functions reported to date was based on the effects of Sigmar1 ligands (e.g., agonist/antagonist) in non-cardiac cells, and some of these ligands elicited these effects even in Sigmar1 null cells. Therefore, despite the wealth of published literature, the molecular mechanism and function of Sigmar1 in cardiac pathophysiology remained unclear as all reported studies are correlative, limited to pharmacologic approaches using non- selective ligands, and molecular mechanisms remained unknown. To determine the molecular function of Sigmar1 in the heart under physiological and pathophysiological conditions, my laboratory recently generated cardiac-specific Sigmar1 transgenic mouse and Sigmar1 conditional knockout mouse models. The central hypothesis of this proposal is that Sigmar1 is cardioprotective and can prevent HF pathogenesis by activating macro-autophagy and mitophagy. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: i) Aim 1 will determine how Sigmar1 activates macro-autophagy and mitophagy in the heart, ii) Aim 2 will determine a novel function for Sigmar1 to protect the heart from ischemic and nonischemic HF. Here, we will use a combination of molecular and biochemical approaches in conjunction with genetically modified mice to define the physiological role of Sigmar1 in protecting the heart from pathological remodeling in response to cardiac injury. As a result, we will be able to determine Sigmar1-mediated autophagy regulatory mechanisms in the heart. These studies will uncover new mechanistic perspectives to approach HF therapeutically and will also provide candidates for pharmacologic and genetic targeting.