MR ADIPOSE-O2 QUANTIFICATION AND THE HYPOXIA-DRIVEN INSULIN RESISTANCE HYPOTHESIS

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 DESCRIPTION (provided by applicant): This is an application for a K01 Mentored Research Scientist Award for Dr. Scott Beeman, a postdoctoral research associate in the Mallinckrodt Institute of Radiology at the Washington University School of Medicine. He has a strong background in developing magnetic resonance techniques for non-invasive measurement of diabetes-related physiologic changes. Herein, he seeks to expand his scientific foundation to include specific expertise in the pathophysiology of diabetes and clinical investigation. A primary goal of Dr. Beeman is to become an independent investigator and a leader in diabetes-related imaging research, thus he proposes a career development plan in which he will train with world's experts in metabolism and diabetes (Drs. Abumrad and Klein) and magnetic resonance and biophysics (Drs. Ackerman and Garbow). From Drs. Abumrad and Klein he will learn: (i) the molecular and cellular mechanisms which relate to type 2 diabetes and its pathogenesis, (ii) husbandry, genotyping, and diet-modification techniques used to produce mouse models of type 2 diabetes, (iii) the gold-standard histological and assay techniques used in type 2 diabetes research, (iv) the ethical and legal issues involved in clinical and translational research, (v) clinical study design and subject recruitment, and (vi) clinical techniques required to study obesity and type 2 diabetes in human subjects. From Drs. Ackerman and Garbow he will learn: (i) a deep theoretical understanding of the biophysics which underpin magnetic resonance signals, (ii) magnetic resonance pulse sequence design, and (iii) magnetic resonance hardware development, and (iv) the nuances of managing a major research laboratory. Insulin resistance is a defining feature of type 2 diabetes - an obesity-related disease with severe morbidity and mortality. Recent studies have suggested that adipose tissue hypoxia is a key step in the cascade that leads to systemic insulin resistance. Still, the longitudinal adipose oxygen partial pressure (pO2) profile during pathogenesis of insulin resistance has not yet been resolved. Characterization of adipose pO2 profile during the pathogenesis of insulin resistance would be a major advance in understanding the hypoxia-driven insulin resistance mechanism. The goals of this work are to: (i) develop methodology to non-invasively quantify in vivo adipose oxygen partial pressure (pO2) with magnetic resonance, (ii) characterize adipose pO2 longitudinally during pathogenic expansion of adipose in mice, (iii) demonstrate the hypoxia-driven insulin resistance mechanism in humans, and (iv) show that exercise intervention restores hypoxic adipose normoxia in humans. The larger goal of this proposal is to develop Dr. Beeman into a productive independent investigator. The knowledge obtained during the proposed career development and research plans will provide him the tools to secure R01 funding and thrive as an independent investigator.