Studies of Fox01 in Insulin Resistance and its interaction with PPARgamma

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DESCRIPTION (provided by applicant): The goals of the proposed training are two-fold: i) to provide training and mentoring to prepare Dr. Jane Kim for an independent research career in diabetes and insulin action and ii) to identify physiologically relevant mechanisms of signaling via the FoxOI forkhead transcription factor in the regulation of adipose metabolism. The principal investigator is a NIH-trained pediatric endocrinologist who has also completed a basic science research fellowship at Columbia University, NY. The proposed funding period will enable her to fully develop the research skills necessary to succeed as an independent investigator. Genetic and biochemical evidence from both vertebrate and invertebrate models indicate that FoxOI plays a pivotal role in insulin action. However, its signaling mechanism remains only partially understood. This proposal investigates the role of FoxOI in adipose tissue physiology. This work is particularly relevant to understanding the aberrant signaling events that underlie insulin resistance in diabetes and overweight/obesity, diseases that affect 65% of adults and 16.5% of children in the U.S. The trainee hypothesizes that FoxOI negatively regulates insulin action in adipocytes and that its effect may be explained, at least in part, by the alterations in PPARgamma-mediated signaling. The specific aims include: 1) using adenoviral expression of wild-type and mutant FoxOI transgenes in cultured adipocytes to define their effects on insulin action and to identify novel targets of FoxOI-dependent transcription; 2) investigating the in vivo role of FoxO proteins through the analysis of FoxOI and FoxO4 knockout mice; and 3) generating novel in vivo models with adipose-targeted mutations of FoxOI. These studies will be the first to comprehensively investigate the physiologic role of FoxOI in adipose tissue using complementary in vitro and in vivo approaches. Dr. Jerrold Olefsky will serve as a mentor for Dr. Kim's scientific development at the University of California, San Diego, and his laboratory will provide Dr. Kim with access to an exceptionally diverse intellectual and research environment. Dr. Olefsky is recognized as an outstanding mentor and leader in the field of insulin action and diabetes. This approach will provide Dr. Kim with a solid platform to construct a successful career as an independent scientist and academic pediatric endocrinologist.