De Novo Lipogenesis in Myocardial Dysfunction

项目简介/摘要：本课题旨在培养申请人成为一名独立的心血管医学领域的医师-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亚专业的临床培训。拟议的5年职业发展计划将在克莱·塞门科维奇博士的指导下完善PI的科学技能。Semenkovich博士是生理学和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初期阶段。此外，PI将能够利用华盛顿大学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。本文的研究旨在描述从头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实验室通过成功地培养和表征组织特异性缺失脂肪酸合成酶（FAS）的小鼠，推动了我们对代谢的思考。该系统使人们能够在没有新生成脂质的情况下研究心肌功能，这是以前从未有过的情况。我们建议验证FAS产生的脂质不同于外周细胞的假设，这些脂质在稳态和急性应激条件下都提供关键的信号作用。我们计划通过表征FASKard（心肌中FAS敲除）小鼠来解决这一假设。

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.