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

描述(申请人提供)：本申请中设计的研究旨在使首席研究员Michael Jurczak博士具备必要的技术和科学专业知识，以成为一名独立的调查员，探索线粒体周转的调节及其在维持线粒体完整性和功能方面的作用。具体地说，尤尔查克博士将开发一种方法来测量小鼠体内线粒体的周转率，并应用遗传学和药理学的方法来了解这一过程是如何调控的。由于在年轻人和老年人中线粒体功能受损与胰岛素抵抗的程度密切相关，这些研究有可能阐明线粒体累积损伤的机制，并有助于我们理解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了解来自细胞培养的研究，这些将是第一次研究被认为在体内线粒体周转调节中的关键角色-Parkin、线粒体解偶联和自噬激活-的作用。为此，提出了以下研究：1)通过在小鼠身上验证和应用一种新的稳定同位素方法，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)使用一种新的条件性Parkin缺失模型来评估Parkin在肝脏中的作用。上述工作将由Michael Jurczak博士在耶鲁大学内分泌科内科Gerald Shulman、Gerald Shadel和Akiko Iwaaki博士的监督下进行。这份申请是精心设计的，以便于尤尔查克博士在三年结束时过渡到助理教授 获奖。通过这一奖项，他将扩大他的技术和科学知识基础，生成数据并获得成功成为独立调查员所需的新技能。这些目标将通过他直接参与拟议的研究、定期与他的顾问委员会会面、完成拟议的课程作业和参加特定的科学会议来实现。耶鲁大学内科为开展拟议中的培训提供了理想的环境，舒尔曼博士和内科为尤尔查克博士的成功做出了坚定的承诺。

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.