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，使其成为一名独立的研究者，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博士将开发方法来测量小鼠体内线粒体周转率，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人和老年人的胰岛素抵抗程度密切相关，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细胞培养的研究，这些研究将是第一个解决线粒体周转调节中被认为是关键角色的研究- Parkin，线粒体解偶联和自噬激活-在体内。为此，本文提出以下研究建议：1)通过在小鼠中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在体内线粒体转换调控中的重要性；2)利用一种新的条件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dr。Gerald Shulman， Gerald Shadel和Akiko Iwasaki来自耶鲁大学内分泌科内科。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

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.