This Mentored Research Scientist Development Proposal describes a four-year research and career development program in the field of metabolomics, with a focus on gaining better understanding of metabolic mechanisms of fuel-stimulated insulin secretion and peripheral insulin resistance. The candidate, Dr. Jessica Gooding, aims to launch an independent career as the director of an analytical core with an emphasis on metabolomics and systems biology. Her research program and mentorship team will provide the training necessary to 1) build mastery in a variety of metabolomics techniques and related statistical methods in the context of complex biological systems 2) develop business and communication skills relevant to directing a core facility and 3) successfully compete for positions and NIH funding. The Stedman Nutrition and Metabolism Center at Duke University, which includes a metabolomics core facility, provides a stimulating environment conducive to meeting these goals. An advisory committee of Dr. Christopher B. Newgard (Mentor), Deborah M. Muoio (Co-mentor), Xianlin Han (Co-mentor). Matthew Hirschey, Svati Shah, James Bain, and Robert Stevens will provide mentorship and expertise in the areas of insulin secretion, insulin resistance, lipidomics, sirtuin biology, biostatistics, and metabolomics method development and laboratory management, respectively. The research plan aims to 1) expand on my current repertoire of techniques;2) complete two mechanistic studies utilizing targeted techniques with the purpose of (a) understanding the mechanism of changes in purine metabolite levels as a result of glucose stimulated insulin secretion (GSIS), and (b) characterizing the energy state of models of insulin resistance and impaired exercise endurance;and 3) leverage this repertoire of metabolomics techniques to understand the metabolic link between sirtuin proteins and insulin secretion. Preliminary data supports each of these aims. Each of these mechanistic studies have the potential to identify new pathways involved in insulin secretion and glucose intolerance and lead to new targets for control of diabetes.

Public Health Relevance

Diabetes affects 25.8 million people in the United States and is the leading cause of kidney failure, non-traumatic lower-limb amputations, and new cases of blindness in adults. Meanwhile, the cost of medical care for persons with diabetes in the US totals $116 billion. The studies proposed here have the potential to identify new pathways involved in insulin secretion and glucose intolerance and lead to new targets for the control of diabetes, and will also train the applicant for an independent career in metabolomics and related disciplines.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Scientist Development Award - Research & Training (K01)
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Special Emphasis Panel (ZRG1)
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Okita, Richard T
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Duke University
Schools of Medicine
United States
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Jensen, Mette V; Gooding, Jessica R; Ferdaoussi, Mourad et al. (2017) Metabolomics applied to islet nutrient sensing mechanisms. Diabetes Obes Metab 19 Suppl 1:90-94
Gooding, Jessica R; Jensen, Mette V; Newgard, Christopher B (2016) Metabolomics applied to the pancreatic islet. Arch Biochem Biophys 589:120-30
Gooding, Jessica R; Jensen, Mette V; Dai, Xiaoqing et al. (2015) Adenylosuccinate Is an Insulin Secretagogue Derived from Glucose-Induced Purine Metabolism. Cell Rep 13:157-167
Todor, Horia; Gooding, Jessica; Ilkayeva, Olga R et al. (2015) Dynamic Metabolite Profiling in an Archaeon Connects Transcriptional Regulation to Metabolic Consequences. PLoS One 10:e0135693
Bustamante-Marin, Ximena M; Cook, Matthew S; Gooding, Jessica et al. (2015) Left-Biased Spermatogenic Failure in 129/SvJ Dnd1Ter/+ Mice Correlates with Differences in Vascular Architecture, Oxygen Availability, and Metabolites. Biol Reprod 93:78
Seiler, Sarah E; Koves, Timothy R; Gooding, Jessica R et al. (2015) Carnitine Acetyltransferase Mitigates Metabolic Inertia and Muscle Fatigue during Exercise. Cell Metab 22:65-76