HARNESSING THE LYSOSOME MACHINERY IN MACROPHAGES TO PREVENT HEART FAILURE

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Project summary This career development proposal has been engineered for the training of the principle investigator (PI) into an independent physician-scientist. The PI has prior basic and translational research experience including a PhD in molecular genetics and cell biology (Dr. Stephen J. Kron) and postdoctoral fellowship in lipoprotein metabolism and macrophage cholesterol efflux (Dr. Daniel J. Rader), culminating in first-author publications at each phase of training. The prior studies of the PI in macrophage cholesterol metabolism have motivated interests in the basic role of macrophages in heart failure due to myocardial infarction, a major public health problem. The PI is a heart failure transplant cardiologist and Clinical Instructor who trained in Internal Medicine (Massachusetts General Hospital), Cardiovascular Diseases, and Advanced Heart Failure and Cardiac Transplantation fellowship (both at University of Pennsylvania, Dr. Kenneth B. Margulies). Both prior clinical and research experiences of the PI motivated the formulation of this 5-year career development program to provide formal training in macrophage immunology and further laboratory training in coronary injury and animal models of heart failure. The main hypothesis of the research proposal is that augmenting the macrophage lysosomal machinery will prevent heart failure due to myocardial infarction. Preliminary studies from the PI indicate that macrophage-specific overexpression of transcription factor EB (TFEB), a master regulator of the autophagy- lysosome pathway, prevents myocardial remodeling after experimental myocardial infarction. The PI will explore this hypothesis and confirm the preliminary results by detailed cardiac phenotyping and assessment of myocardial function in male and female mice (Aim 1), detailed analysis of the myocardial inflammatory response (Aim 2), and investigation into basic subcellular mechanisms by which TFEB may improve macrophage survival and augment anti-inflammatory responses (Aim 3). Completion of the aims will provide the PI necessary training to achieve scientific independence, including further training in cardiac injury models (Aim 1), and macrophage immunology (Aims 2 and 3). Dr. Abhinav Diwan, an expert in modeling lysosome biology in heart failure, will serve as the primary mentor, while Dr. Gwendalyn Randolph, a leading expert in macrophage immunology, will serve as the co-mentor. The PI will benefit from this mentorship team and the tremendous basic and translational resources available at Washington University, a premier academic institution, with an exceptionally strong commitment to training physician-scientists. In addition, during the course of this award, the PI will complete graduate courses in immunology, travel to scientific meetings, and benefit from the input of a career advisory committee composed of the Drs. Diwan and Randolph, as well as Dr. Douglas Mann, a recognized expert in heart failure, Dr. Stuart Kornfeld, a lysosome biologist who has trained over 100 graduate student and postdoctoral fellows, and Dr. Marco Colonna, an internationally-regarded expert in immunology. This application fulfills the immediate training objectives of the PI to acquire expertise in the immuno-biology of heart failure, and the long-term goal of becoming an independent physician-scientist focused on cardiovascular disease research.