DESCRIPTION (provided by applicant): The proposed career development plan is designed to provide the PI with a unique skill set and expertise to meet the career goal of establishing and leading a multidisciplinary bioengineering research group that will be primarily focused on the mechanisms underlying regulation of energy homeostasis and aimed at the identification of therapeutic targets and the development of novel treatments to treat obesity and diabetes. The plan will be carried out at Massachusetts General Hospital, one of the most outstanding and stimulating research environments, with a rich history of interdisciplinary research in diabetes, obesity, and bioengineering. The PI will be mentored by Dr. Martin Yarmush, renowned expert in bioengineering and metabolism, and co-mentored by Dr. David Sabatini (MIT) and Dr. Richard Hodin (MGH and HMS), well established experts in cell biology and intestinal homeostasis, respectively. The central hypothesis to be tested in this application is that Roux-en-Y gastric bypass (RYGB) surgery regulates glucose homeostasis, in part, by triggering a profound metabolic reprogramming in the intestine. The hypothesis has been formulated on the basis of our recent preliminary results and publication which demonstrate a significant increase in the intestinal glucose utilization and cellular proliferation following RYGB. In aim 1, we will employ the rat model of RYGB and perform FDG PET/CT to determine the rate of the increased glucose metabolism in each intestinal segment (e.g. duodenum, jejunum, and ilium) for up to six months post-RYGB. The association between the increased intestinal glucose utilization - as well as weight loss - with the improvement in systemic glucose homeostasis and energy expenditure will also be determined. In aim 2, we will determine the alterations in the rate of cellular proliferation in the intestinal segments following RYGB and characterize the changes in the key signaling pathways that regulate cellular growth and proliferation (particularly PI3K/AKT/mTOR pathway). We will also identify, using immunostaining for GLUT1, the cell type(s) that are predominantly involved in the post-surgical intestinal remodeling. The goal of Aim 3 is to delineate the mechanism underlying the induction of intestinal remodeling: we will determine whether mechanical stimulation of the jejunum due to the passage of undigested food underlies enhanced cellular proliferation. First, by local infusion of diet into different segmentsor Roux-en-Y limbs, we will determine whether mechanical stimulation is necessary and/or sufficient for RYGB to fully induce its therapeutic effects. Next, we will use several complimentary approaches to expose the intestine to mechanical load ex vivo and in vivo and, by pharmacological inhibition of different pathways underlying proliferation and mechanotransduction, we will discern the role of mechanical load in the intestinal remodeling. Collectively, these results will shed light into mechanisms through which RYGB regulates glucose and energy homeostasis which is expected to provide targets for the development of novel treatments to combat diabetes and obesity. Furthermore, the proposed research and training plans will provide the PI with unique training in cell biology and intestinal homeostasis by experts in both fields.

PUBLIC HEALTH RELEVANCE: With over 66% of adult Americans being overweight or obese, the United States is at the epicenter of the obesity pandemic. The goal of this application is to shed light on the mechanisms underlying the resolution of diabetes following Roux-en-Y Gastric Bypass surgery. Specifically, we will focus on the role of intestine in the regulation of glucose and energy homeostasis following the surgery. Upon successful completion of the proposed research, the results will provide new targets and strategies for the development of novel, less-invasive, anti-diabetes and anti-obesity therapies.