Changes in Glutamine/Glutamate Metabolism as a Novel Cardiometabolic Risk Factor

Beth Israel Deaconess Medical Center, Boston MA

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Abstract

DESCRIPTION (provided by applicant): Dr. Andre Dejam is currently a cardiology fellow in research training, whose goal is to become an independent investigator with expertise in metabolomics, integrative physiology in small animals and humans. His passion is to study metabolic disease holistically combining sophisticated physiologic investigations with comprehensive metabolite profiling. His career development plan leverages the resources of a world-class environment by bringing together an outstanding team of investigators centered at two leading academic institutions in Boston; the Massachusetts General Hospital and Beth Israel Deaconess Medical Center. Dr. Dejam has already ob- tained preliminary results demonstrating the feasibility of the research plan that uses a novel metabolomic plat- form that can analyze more than 400 key metabolites from a single sample. Preliminary results performing such analyses in two separate community based cohorts (Framingham Heart Study and Malmo Diet Cancer study) show that individuals with metabolic risk factors have higher circulating concentrations of glutamate and lower levels of glutamine. Since glutamine and glutamate are in a precursor-product relationship via the enzyme glutaminase, we also examined the glutamine-to-glutamate ratio and found that an excess of glutamine relative to glutamate in the circulation was associated with a reduced risk of future type II diabetes mellitus (DMII). These preliminary examinations open several questions for further investigation. Does glutamine exert biological effects on glucose homeostasis in man both acutely (on the same day) and chronically (over a period of two weeks)? What is the biological mechanism by which early stages of the cardiometablic syndrome (CMS) changes glutamine and glutamate levels in opposite directions? And lastly, how does glutamine exert its salutary effects on glucose homeostasis? Under the mentorship of Dr. Robert Gerszten and Drs. Anthony Rosenzweig and the advisors Drs. Thomas Wang, Lewis Cantley, and Anthony Hollenberg, Dr. Dejam proposes to answer all of these questions and proposes: (i) glutamine is intrinsically biologically active improving glucose homeostasis in man, (ii) that an increase in hepatic glutaminase activity in model systems leads to changes in glutamine/glutamate levels hastening insulin resistance, and (iii) that activation of the PI3K-Akt pathway is linked to glutamine's improvement of glucose tolerance. Bringing together cutting-edge technology and a team with relevant expertise, this project will open new avenues for diagnosis of the cardiometablic syndrome and will identify key pathophysiologic pathways that may serve as therapeutic targets in the future. This well-defined translational research proposal, in concert with mentorship and a structured didactic curriculum, will provide Dr. Dejam with the skills that are essential for him to develop an independent career as an investigator interested in metabolic diseases at the cutting edge of science.