The candidate is a board-certified internist specializing in lipidology, starting a career in translational research focused on lipoprotein metabolism, its pathophysiology, and treatment. His short-term goal is mentored support to complete essential formal and practical training supporting his long-term goal, to develop into an independent academic investigator performing high-quality mechanistically-oriented patient-oriented research advancing lipid science and atherosclerosis prevention. Key skills are directed at probing mechanisms, including the use of pharmacologic and physiologic challenges and molecular techniques. The candidate will gain a working knowledge of the proper application of these skills and a publication record in their use, helping him to compete as an independent researcher. This training will enhance the clinical trials of the research project, and include two provocative nutrient challenges, pharmacodynamic modeling, and mRNA expression of clinical samples using in situ hybridization and RT-PCR. Specific hypotheses related to Niacin's Effects on Fatty Acids and Inflammatory Markers (NEFA-IM) are assessed using a niacin challenge to provoke acute changes in insulin sensitivity and postprandial lipidemia. The overall hypothesis is that free fatty acid rebound following niacin a) mediates niacin-induced insulin resistance, and b) interferes with postprandial triglyceride lowering and HDL raising. Hypotheses are tested .by suppressing the free fatty acid rebound with a prostaglandin synthesis inhibitor. Two clinical trials evaluate subjects with metabolic syndrome, a) during an intravenous glucose challenge, and b) an oral fat tolerance test. Complementary analyses include ex vivo analyses from clinical samples evaluated with molecular techniques, in collaboration with appropriate specialists. Advisors are established researchers with expertise related to the major aims, and a history of successful mentorship in an environment known for its emphasis on translational medicine of the kind proposed. This award will help the candidate develop needed skills and preliminary data to support an application for traditional funding that would translate promising findings into the clinical therapy setting.

Public Health Relevance

Niacin is effective at treating high cholesterol and preventing heart attacks, but sometimes raises blood sugar. The purpose of this study is to test a technique that may prevent changes in sugar and even improve cholesterol lowering by niacin. If this is successful, it may lead to future strategies to improve niacin therapy.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZHL1-CSR-R (F1))
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Scott, Jane
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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Dunbar, Richard L; Movva, Rajesh; Bloedon, LeAnne T et al. (2017) Oral Apolipoprotein A-I Mimetic D-4F Lowers HDL-Inflammatory Index in High-Risk Patients: A First-in-Human Multiple-Dose, Randomized Controlled Trial. Clin Transl Sci 10:455-469
Dunbar, Richard L; Goel, Harsh; Tuteja, Sony et al. (2017) Measuring niacin-associated skin toxicity (NASTy) stigmata along with symptoms to aid development of niacin mimetics. J Lipid Res 58:783-797
Goel, Harsh; Dunbar, Richard L (2016) Niacin Alternatives for Dyslipidemia: Fool's Gold or Gold Mine? Part II: Novel Niacin Mimetics. Curr Atheroscler Rep 18:17
Dunbar, Richard L; Goel, Harsh (2016) Niacin Alternatives for Dyslipidemia: Fool's Gold or Gold Mine? Part I: Alternative Niacin Regimens. Curr Atheroscler Rep 18:11
Dunbar, Richard L; Nicholls, Stephen J; Maki, Kevin C et al. (2015) Effects of omega-3 carboxylic acids on lipoprotein particles and other cardiovascular risk markers in high-risk statin-treated patients with residual hypertriglyceridemia: a randomized, controlled, double-blind trial. Lipids Health Dis 14:98
Maki, Kevin C; Orloff, David G; Nicholls, Stephen J et al. (2013) A highly bioavailable omega-3 free fatty acid formulation improves the cardiovascular risk profile in high-risk, statin-treated patients with residual hypertriglyceridemia (the ESPRIT trial). Clin Ther 35:1400-11.e1-3
Degoma, Emil M; Davis, Mat D; Dunbar, Richard L et al. (2013) Discordance between non-HDL-cholesterol and LDL-particle measurements: results from the Multi-Ethnic Study of Atherosclerosis. Atherosclerosis 229:517-23
deGoma, Emil M; Dunbar, Richard L; Jacoby, Douglas et al. (2013) Differences in absolute risk of cardiovascular events using risk-refinement tests: a systematic analysis of four cardiovascular risk equations. Atherosclerosis 227:172-7
DeGoma, Emil M; French, Benjamin; Dunbar, Richard L et al. (2012) Intraindividual variability of C-reactive protein: the Multi-Ethnic Study of Atherosclerosis. Atherosclerosis 224:274-9
Usman, M Haris U; Qamar, Arman; Gadi, Ramprasad et al. (2012) Extended-release niacin acutely suppresses postprandial triglyceridemia. Am J Med 125:1026-35

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