This proposal describes a five-year training program for career development in academic cardiovascular medicine for Dr. Benjamin Olenchock. Dr. Olenchock is an M.D.-Ph.D. physician scientist and prior trainee of the NIH-sponsored Medical Scientist Training Program. He has completed clinical training in Cardiovascular Medicine and Critical Care Medicine through American Board of Internal Medicine accelerated research pathway. He is now embarking on a research and career development program under the mentorship of William G. Kaelin, M.D., Professor of Medicine at Harvard Medical School and the Dana Farber Cancer Institute, and member of both the Institute of Medicine and the National Academy of Sciences. Dr. Kaelin is a world-renown researcher in hypoxia and cellular metabolism, and has a long track record of mentoring trainees who go on to successful, independent research careers. Dr. Olenchock's career development plan includes educational resources at Harvard Medical School, the Dana Farber Cancer Institute, and the Massachusetts Institute of Technology. Additional career development support is provided by the Brigham and Women's Hospital Division of Cardiovascular Medicine, where the principle investigator will serve as attending physician in the Cardiac Intensive Care Unit (CICU) during the period of funding. He has developed a clear timeline for publication of his work in peer-reviewed journals, presentations at national meetings, and plans for the development of independent research projects and funding. Dr. Olenchock is interested in developing novel treatment strategies for conditions he treats in the CICU such as myocardial infarction, systolic heart failure, hypoxic respiratory failure, or cardiac arrest. These conditions have a common pathophysiology of impaired oxygen delivery to tissues. He is investigating the mechanisms by which this common pathophysiology-limited oxygen availability- alters cellular metabolism, and specifically the role played by a family of oxygen-sensing enzymes called EglNs. He has found that inhibition of EglN1 protects against cell death after cardiac ischemia- reperfusion injury. Using an unbiased systems biology approach known as metabolic flux analysis, he has identified metabolic pathways that are unexpectedly regulated by EglN enzymes. The research proposed in his application will build on his preliminary data and explore the relevance of these metabolic effects of EglN1 in a preclinical model of cardiac arrest.
The specific aims of the research proposed in this application are to (1) determine how EglN1 regulates glucose oxidation and cellular respiration (2) develop an in vivo model of metabolic flux analysis and determine how EglNs regulate cardiac metabolism and (3) determine if EglN inhibition is an effective treatment for cardiac arrest.

Public Health Relevance

Many human diseases, including heart attacks, systolic heart failure, respiratory failure, or cardiac arrest, involve impairments of oxygen delivery to the cell of the body. The research proposed in this application will advance our understanding of how cells alter their metabolism in order to survive periods of limited oxygen availability. Additionaly, the proposed experiments will test the efficacy of an entirely new treatment in a preclinical model of cardiac arrest.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZHL1)
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Carlson, Drew E
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Brigham and Women's Hospital
United States
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Sinha, Indranil; Sakthivel, Dharaniya; Olenchock, Benjamin A et al. (2017) Prolyl Hydroxylase Domain-2 Inhibition Improves Skeletal Muscle Regeneration in a Male Murine Model of Obesity. Front Endocrinol (Lausanne) 8:153
Olenchock, Benjamin A; Rathmell, Jeffrey C; Vander Heiden, Matthew G (2017) Biochemical Underpinnings of Immune Cell Metabolic Phenotypes. Immunity 46:703-713
Johnson, Douglas B; Balko, Justin M; Compton, Margaret L et al. (2016) Fulminant Myocarditis with Combination Immune Checkpoint Blockade. N Engl J Med 375:1749-1755
Berg, David D; Sukul, Devraj; O'Brien, Molly et al. (2016) Outcomes in patients undergoing percutaneous ventricular assist device implantation for cardiogenic shock. Eur Heart J Acute Cardiovasc Care 5:108-16
Davidson, Shawn M; Papagiannakopoulos, Thales; Olenchock, Benjamin A et al. (2016) Environment Impacts the Metabolic Dependencies of Ras-Driven Non-Small Cell Lung Cancer. Cell Metab 23:517-28
Olenchock, Benjamin A; Moslehi, Javid; Baik, Alan H et al. (2016) EGLN1 Inhibition and Rerouting of ?-Ketoglutarate Suffice for Remote Ischemic Protection. Cell 164:884-95
Lorenzo, Felipe R; Huff, Chad; Myllymäki, Mikko et al. (2014) A genetic mechanism for Tibetan high-altitude adaptation. Nat Genet 46:951-6
Fendt, Sarah-Maria; Bell, Eric L; Keibler, Mark A et al. (2013) Reductive glutamine metabolism is a function of the ?-ketoglutarate to citrate ratio in cells. Nat Commun 4:2236
Olenchock, Benjamin A; Vander Heiden, Matthew G (2013) Pyruvate as a pivot point for oncogene-induced senescence. Cell 153:1429-30