Gastrointestinal Weight Loss Surgery Regulates Glucose Metabolism via Intestinal Metabolic Remodeling

胃肠减肥手术通过肠道代谢重塑调节葡萄糖代谢

• 批准号: 9285792
• 负责人: Nima Saeidi
• 金额: $ 16.02万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9285792
• 关键词: Adult; American; Animals; Biomedical Engineering; Blood Glucose; Body Weight; Body Weight decreased; Cell Proliferation; Cells; Cellular biology; Consumption; Data; Development; Development Plans; Diabetes Mellitus; Diet; Duodenum; Energy Metabolism; Environment; Exposure to; FRAP1 gene; Food; Gastric Bypass; General Hospitals; Glucose; Goals; Homeostasis; Hormonal Change; Hypertrophy; Infusion procedures; Interdisciplinary Study; Intervention; Intestines; Investigation; Lead; Light; Limb structure; MAPK3 gene; Massachusetts; Mechanical Stimulation; Mechanics; Mediating; Mediator of activation protein; Mentors; Metabolic; Metabolism; Modeling; Molecular; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Operative Surgical Procedures; Organ; Outcome; Overweight; PET/CT scan; PI3K/AKT; PTK2 gene; Pathway interactions; Pharmacology; Physiological; Play; Publications; Rattus; Recording of previous events; Regulation; Regulator Genes; Research; Research Training; Resolution; Role; S-Phase Fraction; SLC2A1 gene; Signal Pathway; Testing; Therapeutic Effect; Therapeutic Intervention; Time; TimeLine; Training; Transcription Factor AP-1; United States; Work; bariatric surgery; base; blood glucose regulation; career; career development; cell growth; cell type; combat; design; fluorodeoxyglucose; fluorodeoxyglucose positron emission tomography; gastrointestinal; glucose metabolism; ilium; improved; in vivo; intestinal homeostasis; jejunum; laser capture microdissection; mechanical load; mechanotransduction; metabolic phenotype; multidisciplinary; novel; obesity treatment; pandemic disease; public health relevance; skills; therapeutic target

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.

描述（由申请人提供）：拟定的职业发展计划旨在为PI提供独特的技能和专业知识，以实现建立和 领导一个多学科的生物工程研究小组，该小组将主要关注能量稳态调节的机制，并旨在确定治疗靶点和开发治疗肥胖和糖尿病的新疗法。该计划将在马萨诸塞州总医院进行，该医院是最杰出和最具刺激性的研究环境之一，在糖尿病、肥胖和生物工程领域拥有丰富的跨学科研究历史。PI将由著名的生物工程和代谢专家Martin Yarmush博士指导，并由大卫萨巴蒂尼博士（麻省理工学院）和理查德霍丁博士（MGH和HMS）共同指导，他们分别是细胞生物学和肠道稳态方面的知名专家。在本申请中待测试的中心假设是Roux-en-Y胃旁路术（RYGB）手术部分地通过触发肠中的深刻代谢重编程来调节葡萄糖稳态。该假设是根据我们最近的初步结果和出版物制定的，这些结果和出版物证明了RYGB后肠道葡萄糖利用和细胞增殖的显着增加。在目的1中，我们将使用RYGB大鼠模型并进行FDG PET/CT以确定RYGB后长达六个月的每个肠段（例如十二指肠、空肠和髂骨）中葡萄糖代谢增加的速率。还将确定肠道葡萄糖利用增加-以及体重减轻-与全身葡萄糖稳态和能量消耗改善之间的关联。在目标2中，我们将确定RYGB后肠段中细胞增殖速率的变化，并表征调节细胞生长和增殖的关键信号通路（特别是PI 3 K/AKT/mTOR通路）的变化。我们还将使用GLUT 1免疫染色鉴定主要参与术后肠重塑的细胞类型。目的3的目标是描绘诱导肠重塑的机制：我们将确定是否由于未消化食物的通过导致空肠的机械刺激是增强细胞增殖的基础。首先，通过将饮食局部输注到不同的节段或Roux-en-Y肢体中，我们将确定机械刺激是否是RYGB完全诱导其治疗效果所必需的和/或足够的。接下来，我们将使用几种互补的方法将肠暴露于离体和体内的机械负荷，通过药理学抑制不同的增殖和机械转导途径，我们将识别机械负荷在肠重塑中的作用。总的来说，这些结果将揭示RYGB调节葡萄糖和能量稳态的机制，这有望为开发新的治疗方法以对抗糖尿病和肥胖提供目标。此外，拟议的研究和培训计划将为PI提供细胞生物学和肠道稳态方面的独特培训，由这两个领域的专家提供。

项目成果

Mechanoscopy: A Novel Device and Procedure for in vivo Detection of Chronic Colitis in Mice.

机械镜检查：一种用于体内检测小鼠慢性结肠炎的新型装置和程序。

• DOI: 10.1093/ibd/izac046
• 发表时间: 2022
• 期刊: Inflammatory bowel diseases
• 影响因子: 4.9
• 作者: He,Shijie;Azar,DaraA;Esfahani,FaridNasr;Azar,GolaraA;Shazly,Tarek;Saeidi,Nima
• 通讯作者: Saeidi,Nima