Parkin's role in hepatic mitochondrial turnover, steatosis and insulin resistance

描述（由申请人提供）：本申请中设计的研究旨在为首席研究员 Michael Jurczak 博士提供必要的技术和科学专业知识，使其成为一名独立研究者，探索线粒体周转的调节及其在维持线粒体完整性和功能中的作用。具体来说，Jurczak 博士将开发测量小鼠体内线粒体周转率的方法，并应用遗传和药理学方法来了解这一过程是如何调节的。由于线粒体功能受损与年轻和老年受试者的胰岛素抵抗程度密切相关，因此这些研究有可能阐明线粒体累积损伤的机制，并有助于我们了解 2 型糖尿病的发病机制。此外，由于我们目前对线粒体周转的理解来自于细胞培养的研究，因此这些将是第一个研究被认为是线粒体周转调节关键因素（Parkin、线粒体解偶联和自噬激活）在体内的作用的研究。为此，提出以下研究：1）通过在小鼠中验证和应用新型稳定同位素方法，评估Parkin、线粒体解偶联和自噬对体内线粒体周转调节的重要性； 2）使用条件性 Parkin 缺失的新模型评估 Parkin 在肝脏中的作用。上述工作将由 Michael Jurczak 博士在 Drs. 的监督下进行。耶鲁大学内科内分泌科的 Gerald Shulman、Gerald Shadel 和 Akiko Iwasaki。该应用程序经过精心设计，旨在帮助 Jurczak 博士在三年结束时过渡为助理教授 奖。通过这个奖项，他将扩大他的技术和科学知识基础，生成数据并获得作为独立调查员取得成功所需的新技能。这些目标将通过他直接参与拟议的研究、定期与顾问委员会会面、完成拟议的课程作业和参加特定的科学会议来实现。耶鲁大学内科为接受拟议的培训提供了理想的环境，舒尔曼博士和该部门坚定地致力于 Jurczak 博士的成功。

DESCRIPTION (provided by applicant): The studies designed in this application are intended to equip the principal investigator, Dr. Michael Jurczak, with the technical and scientific expertise necessary to become an independent investigator exploring the regulation of mitochondrial turnover and its role in maintaining mitochondrial integrity and function. Specifically, Dr. Jurczak will develop methodology to measure rates of mitochondrial turnover in mice in vivo and apply genetic and pharmacological approaches to understand how this process is regulated. Because impaired mitochondrial function is strongly associated with the degree of insulin resistance in both young and old human subjects, these studies have the potential to elucidate a mechanism by which mitochondria accumulate damage and contribute to our understanding of the pathogenesis of type 2 diabetes. Also, because our current understanding of mitochondrial turnover comes from studies in cell culture, these would be the first studies to address the role of what are thought of as key players in the regulation of mitochondrial turnover - Parkin, mitochondrial uncoupling and activation of autophagy - in vivo. To this end, the following studies are proposed: 1) evaluate the importance of Parkin, mitochondrial uncoupling and autophagy to the regulation of mitochondrial turnover in vivo by validating and applying a novel stable isotope approach in mice; 2) evaluate the role of Parkin in liver using a novel model of conditional Parkin deletion. The above work will be carried out by Dr. Michael Jurczak under the supervision of Drs. Gerald Shulman, Gerald Shadel and Akiko Iwasaki in the Department of Internal Medicine, Section of Endocrinology at Yale University. This application was carefully designed to facilitate Dr. Jurczak's transition to Assistant Professor at the end of the three year award. Through this award, he will broaden his technical and scientific knowledge base, generate data and acquire new skills necessary to succeed as an independent investigator. These goals will be met through his engaging directly in the proposed research, by meeting regularly with his advisory committee, completing proposed coursework and attending specific scientific meetings. The Department of Internal Medicine at Yale provides an ideal environment to pursue the proposed training and Dr. Shulman and the Department are deeply committed to Dr. Jurczak's success.