A BRD4-GATA4 module cooperatively regulates mitochondrial bioenergetic homeostasis in the adult heart

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PROJECT SUMMARY / ABSTRACT Heart failure (HF) affects millions of people and costs over 40 billion dollars annually in the United States alone. Despite current pharmacotherapeutic approaches, which largely involve blockade of circulating neurohormone activity, a diagnosis of HF carries a 5‐year mortality rate of nearly 50% underscoring the urgent need for new treatments. The mitochondria have emerged as a central factor in the pathogenesis and progression of HF with no therapies presently available to address mitochondrial dysfunction. My goal in seeking a K08 Mentored Clinical Scientist Research Career Development Award is to acquire the necessary knowledge and practical training to make major advances in our understanding of the mechanisms underlying cardiac energy metabolism and mitochondrial function in the adult heart. I hypothesize that BRD4 (a ubiquitously expressed chromatin “reader” protein) complexes with GATA4 (a lineage determining cardiac transcription factor) to regulate a mitochondrial bioenergetic gene program in cardiomyocytes (Aim 1). I also hypothesize that GATA4 is a critical regulator of cardiac metabolism in cardiomyocytes in vivo and that this tissue-enriched transcription factor is providing specificity to the action of BRD4 (Aim 2). Finally, I hypothesize that a BRD4-GATA4 module controls the expression of PGC-1α and β, known master transcriptional regulators of mitochondrial genes, to mediate the phenotype of cardiomyocyte BRD4 loss (Aim 3). To address these aims, I will combine novel animal models that I have generated, standard in vitro biochemical approaches, and advanced molecular biology and bioinformatics techniques. My long-term goal is to develop a deeper molecular understanding of HF pathogenesis that may lead to novel therapies. My graduate training provided me with important experience in cardiovascular research, however my focus was on developmental biology. I am now directing my efforts towards studying adult cardiomyocyte homeostasis—an area of interest that emerged from my clinical training in cardiology. My research mentor has a long record of impactful discoveries using cutting-edge techniques in cellular and animal models of cardiovascular disease. The research environment at the Gladstone Institutes/UCSF is exceptional and houses state-of-the-art equipment and investigators making groundbreaking discoveries. I have assembled a team of highly accomplished mentors and advisors to guide me through this next phase of my training on the path to becoming an independent investigator. My training plan is specifically designed to provide me with mentorship and research training in bioinformatics, mouse modeling of disease, and advanced techniques in molecular biology. Beyond this, I will gain experience with other skills required to run a research group, such as scientific communication and laboratory management. Completing the research and obtaining the skill sets outlined in this proposal will prepare me well to obtain R01 or equivalent funding to begin my career as an independent investigator.