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 for my independent career. A central part of the intramural phase of the K22 award will be my Advisory Committee that will evaluate my progress on the proposed research and career development training as outlined in the detailed Career Development Plan. The advisory committee composed of intramural and extramural members will provide continuous guidance. The scientific training will support the proposed Specific Aims through a combination of specialized course work and hands-on training to complete the proposed innovative Research Strategy. Importantly, the techniques and approaches developed during the funding period of the award will not only advance our understanding of physiological role of cardiac mitophagy, but also allow for the successful completion of the proposed Research Strategy. This will establish the basis of my first NIH R01 and additional independent funding applications. I will also undertake extensive career and professional training in the intramural phase of this award to help master academic challenges anticipated in the extramural phase of the award. Mentoring and teaching will be complemented with training in management and leadership in the form of seminars and workshops. The professional career development training also involves mentoring of junior scientists, participation in grant- writing workshops, development of communication skills, networking at meetings, career counseling and assessment coaching to prepare for my transition to independence and my long term goal of becoming a successful independent investigator. Cardiovascular disease represents the leading cause of death in the USA, understanding the mechanisms regulating cardiac mitophagy that protect the heart from heart failure and cardiac hypertrophy could prove invaluable to public health. Constitutive mitophagy is a homeostatic mechanism for maintaining mitochondrial quality and global mitochondrial function not only in the heart, but also in other tissues. As my career develops, I envision that I will use the insight I have gained from studying the function of cardiac mitophagy and apply this knowledge to investigate the role of mitophagy in a variety of contexts in other organs and systems, particularly in the brain, where I have demonstrated an important role of mitophagy in neuronal degeneration. In summary, the proposed studies will illustrate the importance of mitophagy in the perinatal and adult heart. These insights may provide the basis for novel therapeutic approaches in a wide variety of heart diseases. In addition, the described career development plan will notably enhance my transition to academic independence and chances for continued scientific success.
Mitochondria generate energy that fuels cardiac contraction and are crucial for heart function. Therefore, it is essential to preserve cardiac mitochondrial function through specific mitochondrial quality control pathways. This project aims to investigate mitophagic flux in the normal and stressed heart, as well as to determine the in vivo role of USP30, a mitochondrial deubiquitinase, and CPT1a, a key mitochondrial enzyme that controls fatty acids ?-oxidation, in regulating cardiac mitophagy. These studies will lead to a greater understanding of how mitochondrial energy metabolism is linked to mitochondrial quality control and may provide new approaches to treat a range of diseases, including heart failure and cardiac hypertrophy.
