Gastrointestinal Weight Loss Surgery Regulates Glucose Metabolism via Intestinal Metabolic Remodeling

描述(由申请人提供)：拟议的职业发展计划旨在为私人投资经理提供独特的技能和专业知识，以满足建立和 领导一个多学科生物工程研究小组，主要专注于能量稳态调节的潜在机制，旨在确定治疗目标和开发治疗肥胖症和糖尿病的新疗法。该计划将在马萨诸塞州综合医院进行，该医院是最杰出和最具启发性的研究环境之一，在糖尿病、肥胖症和生物工程方面有着丰富的跨学科研究历史。PI将由著名的生物工程和新陈代谢专家Martin Yarmush博士指导，并分别由细胞生物学和肠道动态平衡方面的知名专家David Sabatini博士(麻省理工学院)和Richard Hodin博士(MGH和HMS)共同指导。在这项应用中要检验的中心假设是Roux-en-Y胃旁路(RYGB)手术调节葡萄糖稳态，部分是通过触发肠道内深刻的代谢重新编程。这一假说是基于我们最近的初步结果和发表的，这些结果表明RYGB后肠道葡萄糖利用和细胞增殖显着增加。在目标1中，我们将使用RYGB大鼠模型，并进行FDG PET/CT检查，以确定RYGB术后6个月内各肠段(如十二指肠、空肠和髂骨)葡萄糖代谢增加的比率。肠道葡萄糖利用增加和体重减轻与改善全身葡萄糖稳态和能量消耗之间的关系也将被确定。在目标2中，我们将确定RYGB后肠段细胞增殖率的变化，并表征调控细胞生长和增殖的关键信号通路(特别是PI3K/AKT/mTOR通路)的变化。我们还将通过GLUT1的免疫组织化学染色，确定主要参与手术后肠道重塑的细胞类型(S)。目标3的目标是描述诱导肠道重塑的潜在机制：我们将确定由于未消化的食物通过而对空肠的机械刺激是否支持促进细胞增殖。首先，通过向不同节段的Roux-en-Y肢体局部注入饮食，我们将确定机械刺激是否必要和/或足以使RYGB充分发挥其治疗效果。接下来，我们将使用几种互补的方法来使肠道在体外和体内暴露于机械负荷，并通过药物抑制潜在的增殖和机械转导的不同途径，我们将辨别机械负荷在肠道重塑中的作用。总的来说，这些结果将揭示RYGB调节血糖和能量稳态的机制，这有望为开发抗击糖尿病和肥胖症的新疗法提供靶点。此外，拟议的研究和培训计划将为PI提供这两个领域的专家在细胞生物学和肠道动态平衡方面的独特培训。

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.