De Novo Lipogenesis in Myocardial Dysfunction

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DESCRIPTION (provided by applicant): Project Summary / Abstract: This proposal aims to develop the applicant into an independent physician-scientist in the field of cardiovascular medicine. The principal investigator (PI) has already undergone PhD training in the basic biological sciences and completed clinical training in internal medicine and the cardiology subspecialty. The proposed 5-year career development plan will provide refinement of the PI's scientific skills under the mentorship of Dr. Clay Semenkovich. Dr. Semenkovich is a recognized leader in physiology and metabolism and has a track record for training successful physician-scientists, especially at the incipient stages of their careers. In addition, the PI will be able to take advantage of the enormous breadth of clinical and basic science resources available at Washington University, including obtaining scientific as well as career guidance from his faculty advisory committee and collaborators. The research set forth herein seeks to delineate the unique roles de novo lipogenesis play in myocardial physiology and pathophysiology. In the past few years, the Semenkovich laboratory has advanced our thinking about metabolism by successfully generating and characterizing mice with tissue-specific deletion of fatty acid synthase (FAS). This system enables one to study myocardial function in the absence of de novo-generated lipids, a situation that has never before been possible. We propose to test the hypothesis that FAS acts to generate lipids distinct from those obtainable from the periphery and that these lipids provide critical signaling roles under both homeostatic and acute stress conditions. We plan to address this hypothesis by characterizing FASKard (FAS Knockout in the Myocardium) mice. PUBLIC HEALTH RELEVANCE: Project Narrative: This career development plan has two long-lasting goals. First, it will serve to develop an individual with both research and clinical expertise in the cardiovascular sciences, a career-path that is currently on the wane but critically important for future breakthroughs. Second, the paradigm-shifting concept that endogenous and exogenous lipids have distinct roles in physiology and metabolism is an emerging one and one that is sure to be of critical importance in our understanding of cardiac function in both normal and pathological states.