Padmanabhan K08 Admin Supplement

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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 was 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. With an unusual degree of irony, I suffered a myocardial infarction in October, 2022 that was complicated by a diagnosis of HF which has slowed my progress in carrying out the aims described in my initial proposal. I am hopeful that the additional funding afforded by this Administrative Supplement will allow me to close the gap in productivity that resulted from this critical life event. Those aims are centered around the hypotheses that 1.) the ubiquitously expressed chromatin reader protein BRD4 complexes with the cardiac transcription factor GATA4 to regulate mitochondrial bioenergetic gene programs in cardiomyocytes; 2.) 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; and 3.) that a BRD4-GATA4 module controls the expression of PGC-1a and b, known master transcriptional regulators of mitochondrial genes, to mediate the phenotype of cardiomyocyte BRD4 loss. To address those aims, I have been combining novel animal models that I have generated, standard in vitro biochemical approaches, and advanced molecular biology and bioinformatics techniques. My long-term goal, which is now further motivated by my personal experience with this chronic disease, 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. In light of my recent event, my institution has provided me with additional resources and mentorship to help ensure my continued success such that I can complete the research and obtain the skill sets outlined in the initial K08 proposal, thus preparing me well to obtain R01 or equivalent funding to begin my career as an independent investigator. This Administrative Supplement will aid significantly towards that end and make certain that this unfortunate episode has no lasting adverse professional consequences.