De Novo Lipogenesis in Myocardial Dysfunction

描述（由申请人提供）：项目摘要/摘要：本提案旨在将申请人发展成为心血管医学领域的独立医生-科学家。主要研究者（PI）已经接受了基础生物科学的博士培训，并完成了内科和心脏病学专科的临床培训。拟议的5年职业发展计划将在Clay Semenkovich博士的指导下完善PI的科学技能。Semenkovich博士是生理学和新陈代谢领域公认的领导者，在培养成功的医生科学家方面有着良好的记录，特别是在他们职业生涯的初期阶段。此外，PI将能够利用华盛顿大学提供的广泛的临床和基础科学资源，包括从他的教师咨询委员会和合作者那里获得科学和职业指导。 本文所述的研究旨在描述新生脂肪生成在心肌生理学和病理生理学中的独特作用。在过去的几年里，Semenkovich实验室通过成功地产生和表征组织特异性缺失脂肪酸合酶（FAS）的小鼠，推进了我们对代谢的思考。该系统使人们能够在没有新生脂质的情况下研究心肌功能，这种情况以前从未发生过。我们建议测试的假设，FAS的行为，以产生脂质不同的那些可从周边和这些脂质提供关键的信号作用下的稳态和急性应激条件。我们计划通过表征FASKard（肌内FAS敲除）小鼠来解决这一假设。 公共卫生相关性：项目叙述：该职业发展计划有两个长期目标。首先，它将有助于培养一个在心血管科学方面具有研究和临床专业知识的人，这是一条目前正在衰落但对未来突破至关重要的职业道路。第二，范式转变的概念，内源性和外源性脂质在生理和代谢中有不同的作用是一个新兴的和一个肯定是至关重要的，在我们理解心脏功能的正常和病理状态。

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.