7. Project Summary Mitochondria provide an essential source of energy and play an important role during cardiac development and in heart failure progression. Cumulative evidence illustrates the importance of mitochondrial quality control in cardiac function during fetal life and in the adult heart. This K22 application centers on a research proposal to study the role of cardiac mitophagy, an important aspect of mitochondrial quality control, in both physiological and pathophysiological conditions within the context of a career development program. The program is designed to facilitate a successful transition from postdoctoral training to independent research. These studies will be facilitated by my recently described mt-Keima mouse model to monitor in vivo cardiac mitophagic flux, as well as the use of genetic Parkin deficient (a positive mitophagy regulator) and USP30 deficient (a negative mitophagy regulator) mouse models. This will be supplemented by detailed cardiac functional analysis using murine models of transverse aortic constriction induced cardiomyopathy. In particular, I will determine the role of mitophagy in perinatal cardiac mitochondrial maturation and during cardiac pathological stresses, as well as test a specific USP30 inhibitor in stimulating cardiac mitophagy and in attenuating progression of heart failure (Aim 1). It is increasingly recognized that mitophagy is critical for mitochondrial plasticity and metabolic reprogramming during normal heart development and in various disease conditions. I will further test the hypothesis that the rate limiting enzyme in fatty acid oxidation, CPT1a, may regulate mitophagy. Using a cardiac specific CPT1a knockout mouse, I will assess whether CPT1a regulates the mitochondrial perinatal metabolic transition and the adult mitophagic response that occurs following cardiac stress (Aim 2). Completion of the proposed Research Strategy will produce critical insights into the role of mitophagy in normal cardiovascular physiology and pathological conditions, and will fundamentally advance our understanding of the interaction between mitochondrial metabolism and mitochondrial quality control in the heart. This enhanced understanding of the role of mitophagy, USP30 and CPT1a in the heart should open possibilities for harnessing these pathways for therapeutic potential. These studies will be initiated within the NIH intramural program and completed during an extramural, independent phase. Through this K22 Career Development Award proposal, I seek to systematically acquire additional mentored research training and career development training at the NIH/NHLBI through a detailed Career Development Plan designed to complement my current skill set, including additional formal training in cardiac physiology and pathophysiology. With the continued support of members of my Advisory Committee, the K22 Career Development Award will establish a training framework to initiate the research program in preparation...