Molecular and Cellular Basis for the Efficacy of Bariatric Surgery

减肥手术功效的分子和细胞基础

基本信息

批准号：
8583364
负责人：
Naji N Abumrad
金额：
$ 61.2万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-16 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8583364
关键词：
20 year old Ablation Achievement Address Adult American Anatomy Animal Model Applications Grants Bariatrics Biological Models Body Weight decreased Brain Bypass Candidate Disease Gene Canis familiaris Cardiovascular system Cell Lineage Cell model Cells Collection Communication Comorbidity Data Data Reporting Development Diabetes Mellitus Diet Eating Effectiveness Endocrine Energy Metabolism Engineering Enteroendocrine Cell Exhibits Failure Family suidae Fatty acid glycerol esters Food Preferences GCG gene Gastrectomy Gastric Bypass Gastroenterology Gene Transfer Techniques Genes Genetic Goals Guidelines Health Homeostasis Hormonal Hormones Human Human Genetics Hunger Hypertension Individual Insulin-Dependent Diabetes Mellitus Intervention Knock-out Label Laboratory mice Lead Maintenance Maps Mediating Metabolic Metabolic syndrome Methods Modality Modeling Molecular Morbid Obesity Morbidity - disease rate Mus Neuronal Plasticity Neurosciences Neurosecretory Systems Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Operative Surgical Procedures Organism Other Genetics Outcome Pathology Patients Peptide Receptor Peptides Peripheral Pharmacologic Substance Physiological Physiology Play Population Preparation Prevalence Procedures Production Publishing Rattus Reporting Research Research Personnel Retinal Cone Rewards Role Satiation Sequence Analysis Signal Pathway Signal Transduction Small Intestines Societies Stomach Study models Synapses System Techniques Technology Testing Transgenic Mice United States National Institutes of Health Variant Weight Weight Gain Work Yin bariatric surgery base blood glucose regulation cell type cohort economic cost effective therapy exome sequencing ghrelin glycemic control hedonic ileum improved insulin sensitivity knockout gene member mortality novel novel therapeutics obesity treatment programs public health relevance response

项目摘要

DESCRIPTION (provided by applicant): Bariatric surgery is currently the only effective treatment for severe obesity, and the only effective cure for type II diabetes. Research on the mechanism of action of the different bariatric surgical procedures in humans and model systems including pigs, dogs, rats, and mice supports the hypothesis that the beneficial effects result from more than the restrictive or malabsorptive effects of the procedures on food intake. Indeed, data argue that neuroendocrine changes in gut-brain signaling resulting from the Roux-en-Y and gastric sleeve procedures alter satiety, hunger, food preferences, and glucose homeostasis prior to the achievement of significant weight loss. Understanding the cellular and molecular basis of these changes induced by bariatric surgery might lead to the development of pharmaceutical interventions, or improved surgical procedures for the treatment of obesity and diabetes. While several animal models can be used for research on the physiology of bariatric surgery, the mouse provides the best model for studies of cellular and molecular mechanisms because transgenesis can be used to alter individual genes, and to label specific cell types. We show results here demonstrating successful creation of murine bariatric surgery models at Vanderbilt, and the use of the models to identify the first gene that plays an essential role in th efficacy of RYGB for long term maintenance of significant weight loss. The unique hypothesis to be tested is that the efficacy of bariatric surgery results not solely from a collection of changesto Gl signaling, but rather that essential changes in both Gl signaling AND in the plasticity and responsiveness of CNS homeostatic and hedonic circuits act synergistically to restore glucose homeostasis, and create a new weight set point. In this interdisciplinary team grant application, we bring together leading experts in human and murine bariatric surgery, murine pathology, Gl anatomy and function, obesity and diabetes, and quantitative human genetics to jointly study surgical preparations from humans and mice in order to identify the genes and cell types mediating the efficacy of bariatric surgery.

描述（由申请人提供）：减肥手术目前是严重肥胖症的唯一有效治疗方法，也是II型糖尿病的唯一有效治愈方法。研究包括猪，狗，大鼠和小鼠在内的人类和模型系统中不同减肥手术程序的作用机理的研究支持了以下假设：有益的作用是由限制性或不良效果对食物摄入的限制性或不良效果产生的。实际上，数据认为，在实现重大体重减轻之前，由roux-en-y和胃袖程序引起的肠脑信号传导的神经内分泌变化改变了饱腹感，饥饿，食物偏爱和葡萄糖稳态。了解减肥手术引起的这些变化的细胞和分子基础可能会导致药物干预的发展，或改善治疗肥胖和糖尿病的手术程序。虽然几种动物模型可用于研究减肥手术的生理学，但小鼠为细胞和分子机制研究提供了最佳模型，因为转基因可用于改变单个基因，并标记特定的细胞类型。我们在这里显示的结果表明，在范德比尔特（Vanderbilt）成功创建了鼠减肥手术模型，并使用模型来识别第一个基因在RYGB在长期维持重大体重减轻方面起着至关重要的作用。要测试的独特假设是，减肥手术的疗效不仅来自Changesto GL信号的集合，而是GL信号传导以及CNS稳态和享乐电路的可塑性和反应性的基本变化，以协同恢复Glucose。稳态，并创建一个新的重量设定点。在此跨学科团队赠款的应用中，我们将人和鼠减肥手术，鼠病理学，GL解剖学和功能，肥胖和糖尿病以及定量人类遗传学的领先专家汇集在一起，以共同研究人类和小鼠的手术准备，以识别基因和细胞类型介导减肥手术的功效。