De Novo Lipogenesis in Myocardial Dysfunction

描述(由申请人提供)：项目摘要/摘要：本建议旨在将申请人培养成心血管医学领域的独立内科医生-科学家。首席研究员(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分专业的临床培训。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。塞门科维奇博士是生理学和新陈代谢领域公认的领导者，在培养成功的内科科学家方面有着良好的记录，特别是在他们职业生涯的早期阶段。此外，PI将能够利用华盛顿大学丰富的临床和基础科学资源，包括从他的教职员工咨询委员会和合作者那里获得科学和职业指导。本研究旨在阐明新生脂肪生成在心肌生理学和病理生理学中所起的独特作用。在过去的几年里，塞门科维奇实验室通过成功地培育并鉴定了组织特异性脂肪酸合成酶(Fas)缺失的小鼠，推动了我们对新陈代谢的思考。这一系统使人们能够在没有新生脂质的情况下研究心肌功能，这是以前从未可能发生的情况。我们建议检验这样一种假设，即Fas的作用是产生不同于从外周获得的那些脂类，并且这些脂类在动态平衡和急性应激条件下都提供关键的信号角色。我们计划通过FASKard(心肌Fas基因敲除)小鼠的特征来解决这一假设。 公共卫生相关性：项目描述：这项职业发展计划有两个长期目标。首先，它将有助于培养在心血管科学方面同时拥有研究和临床专业知识的个人，这是一条目前正在衰落的职业道路，但对未来的突破至关重要。其次，内源性和外源性脂质在生理和新陈代谢中具有不同作用的范式转换概念是一个新兴的概念，对于我们理解正常和病理状态下的心脏功能肯定是至关重要的。

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.