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.

Public Health Relevance

The pathogenesis of type 2 diabetes is incompletely understood, however, data from human studies demonstrate that insulin resistance is strongly associated with mitochondrial dysfunction. Mitochondrial defects are thought to occur due to a mismatch of repair and damage throughout the life of a mitochondrion. The studies described in this application would be the first to measure true rates of mitochondrial turnover, a repair mechanism, in liver of mice in vivo and address the potential role of declining rates of turnover to the development of hepatic insulin resistance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK099402-03
Application #
8846594
Study Section
Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
Program Officer
Spain, Lisa M
Project Start
2013-08-15
Project End
2015-07-31
Budget Start
2015-06-01
Budget End
2015-07-31
Support Year
3
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
Corbit, Kevin C; Camporez, João Paulo G; Edmunds, Lia R et al. (2018) Adipocyte JAK2 Regulates Hepatic Insulin Sensitivity Independently of Body Composition, Liver Lipid Content, and Hepatic Insulin Signaling. Diabetes 67:208-221
Stout, Michael B; Steyn, Frederik J; Jurczak, Michael J et al. (2017) 17?-Estradiol Alleviates Age-related Metabolic and Inflammatory Dysfunction in Male Mice Without Inducing Feminization. J Gerontol A Biol Sci Med Sci 72:3-15
Corbit, Kevin C; Camporez, João Paulo G; Tran, Jennifer L et al. (2017) Adipocyte JAK2 mediates growth hormone-induced hepatic insulin resistance. JCI Insight 2:e91001
Abulizi, Abudukadier; Perry, Rachel J; Camporez, João Paulo G et al. (2017) A controlled-release mitochondrial protonophore reverses hypertriglyceridemia, nonalcoholic steatohepatitis, and diabetes in lipodystrophic mice. FASEB J 31:2916-2924
Costa, Diana K; Huckestein, Brydie R; Edmunds, Lia R et al. (2016) Reduced intestinal lipid absorption and body weight-independent improvements in insulin sensitivity in high-fat diet-fed Park2 knockout mice. Am J Physiol Endocrinol Metab 311:E105-16
Petersen, Max C; Jurczak, Michael J (2016) CrossTalk opposing view: Intramyocellular ceramide accumulation does not modulate insulin resistance. J Physiol 594:3171-4
Petersen, Max C; Madiraju, Anila K; Gassaway, Brandon M et al. (2016) Insulin receptor Thr1160 phosphorylation mediates lipid-induced hepatic insulin resistance. J Clin Invest 126:4361-4371
Camporez, João-Paulo G; Petersen, Max C; Abudukadier, Abulizi et al. (2016) Anti-myostatin antibody increases muscle mass and strength and improves insulin sensitivity in old mice. Proc Natl Acad Sci U S A 113:2212-7
Petersen, Max C; Jurczak, Michael J (2016) Rebuttal from Max C. Petersen and Michael J. Jurczak. J Physiol 594:3177-8
Nagarajan, Arvindhan; Petersen, Max C; Nasiri, Ali R et al. (2016) MARCH1 regulates insulin sensitivity by controlling cell surface insulin receptor levels. Nat Commun 7:12639

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