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使主要研究者Michael Jurczak博士具备成为独立研究者所需的技术和科学专业知识，以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博士将开发方法来测量小鼠体内线粒体的周转率，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人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理解来自细胞培养的研究，这些将是第一个研究解决被认为是线粒体周转调节中的关键参与者的作用-帕金，线粒体解偶联和自噬激活-在体内。为此，提出了以下研究：1）通过在小鼠中验证和应用新的稳定同位素方法来评估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博士在耶鲁大学内科内分泌科Gerald Shulman、Gerald Shadel和Akiko Iwasaki博士的监督下进行。这份申请是精心设计的，以方便Jurczak博士在三年结束时过渡到助理教授。 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，并获得必要的新技能，成功地作为一个独立的调查。这些目标将通过他直接参与拟议的研究来实现，定期与他的咨询委员会会面，完成拟议的课程并参加特定的科学会议。耶鲁大学内科系提供了一个理想的环境，以追求拟议的培训和博士舒尔曼和部门都深深致力于博士Jurczak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.