Role of Ileum in Reducing Obesity Related Comorbidities

回肠在减少肥胖相关合并症中的作用

• 批准号: 7890360
• 负责人: Rohit Kohli
• 金额: $ 15.04万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7890360
• 关键词: ASBT protein; Acids; Adolescent; Adult; Anatomy; Animals; Back; Bariatrics; Bile Acids; Bile fluid; Biliary; Biliopancreatic Diversion; Blood Vessels; Body Weight decreased; CYP7A1 gene; Catheterization; Childhood; Cholesterol; Cholic Acids; Clinical; Coenzyme A; Comorbidity; Data; Diabetes Mellitus; Distal; Enterohepatic Circulation; Fatty Liver; Figs - dietary; Gastric Bypass; Gastroenterologist; Gastrointestinal tract structure; Goals; Hepatic; Hydroxycholesterols; Intervention; Intestinal Absorption; Intestines; Isotopes; K-Series Research Career Programs; Laboratories; Length; Ligaments; Ligands; Link; Lipids; Liver; Malabsorption Syndromes; Mass Fragmentography; Measurement; Measures; Mediating; Medical; Mentors; Metabolic; Metabolism; Modeling; Morbid Obesity; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Nutritional; Obesity; Obesity associated hypercholesterolemia; Operative Surgical Procedures; Oxidoreductase; Pathway interactions; Plasma; Portal vein structure; Positioning Attribute; Prevalence; Procedures; Production; Rattus; Reporting; Research; Resected; Resolution; Role; Serum; Sterols; Stomach; Stress; Surgical Models; Techniques; Testing; Therapeutic; Time; Training; Translating; United States; Weight; Work; absorption; bariatric surgery; bile acid transporter; bile duct; bile salts; cholesterol absorption; experience; feeding; glucose tolerance; hypercholesterolemia; ileum; improved; in vivo; inhibitor/antagonist; jejunum; novel; obesity in children; professor; public health relevance; receptor; research study; reuptake; sham surgery

DESCRIPTION (provided by applicant): The prevalence of obesity is increasing at alarming rates in the United States such that bariatric surgery has become an accepted therapeutic option for adults and adolescents with morbid obesity. Bariatric surgery provides significant metabolic benefits, including resolution of type-2 diabetes and marked reduction in hypercholesterolemia, that precede the weight loss produced by these surgeries. The mechanisms responsible for these weight-independent metabolic benefits are poorly understood. Dr. Kohli's long-term research objective is to characterize the mechanisms behind these weight-loss-independent metabolic benefits of bariatric surgical procedures and translate those observations into more scalable non-invasive therapeutic measures. In this proposal Dr. Kohli will focus on the benefits of bariatric surgery to obesity related hypercholesterolemias by using a unique surgical procedure called "Ileal Transposition" in a rat model. This weight loss surgery has been previously shown to produce improved glucose tolerance similar to roux-en-y- gastric bypass without gastric size restriction or malabsorption. Dr. Kohli has generated exciting preliminary data using this surgical model that include a significant reduction in cholesterol levels that is independent of weight loss. The specific aims of his proposal will examine the mechanistic links between bile acid entero-hepatic circulation and cholesterol absorption, sensing, and endogenous production in this bariatric surgery model. He will also investigate the role of adaptation of the transposed segment of the ileum in reduction of cholesterol. These studies build on Dr. Kohli's prior work as a fellow investigating the mechanisms involved in lipid-induced nutritional stress producing hepatic steatosis. The primary goal of this mentored career development award is to provide a pathway for Dr. Kohli, a trained pediatric gastroenterologist and hepatologist, to achieve scientific independence. By developing an expertise in lipid and bile acid metabolism using small-animal surgical-obesity-intervention models, he will distinguish himself from his mentor, Professor Randy Seeley, and be well-positioned to make significant scientific and medical contributions to the understanding of obesity in children and adolescents. PUBLIC HEALTH RELEVANCE: Bariatric surgery is now an accepted treatment for the morbidly obese adult or adolescent. Certain benefits of these surgeries, such as reduced cholesterol and resolution of diabetes, occur even prior to weight loss. This proposal seeks to identify the key mechanisms involved in these weight-loss-independent improvements in cholesterol levels and then translate those findings to non-invasive more scalable treatment options.

描述（由申请人提供）： 在美国，肥胖症的患病率正在以惊人的速度增加，因此减肥手术已成为患有病态肥胖症的成年人和青少年的公认治疗选择。减肥手术可提供明显的代谢益处，包括分辨率2型糖尿病和高胆固醇血症的明显降低，这是这些手术产生的体重减轻之前。对这些独立的代谢益处负责的机制知之甚少。 Kohli博士的长期研究目标是表征减肥手术程序的这些独立体重代谢益处背后的机制，并将这些观察结果转化为更可扩展的非侵入性治疗方法。在这项建议中，Kohli博士将通过在大鼠模型中使用一种称为“回肠换位”的独特手术程序来关注减肥手术对肥胖相关的高胆固醇的好处。先前已显示这种减肥手术可产生改善的葡萄糖耐受性，类似于Roux-en-Y-Y-胃搭桥，而无需胃大小限制或吸收不良。 Kohli博士使用该手术模型生成了令人兴奋的初步数据，其中包括与体重减轻无关的胆固醇水平的显着降低。他的提案的具体目的将检查该减肥手术模型中胆汁酸肠肝循环与胆固醇吸收，感应和内源性产生之间的机械联系。他还将调查回肠段落段的适应性作用。这些研究基于科利博士的先前工作，研究了脂质诱导的营养应激产生肝脂肪变性的机制。这项指导职业发展奖的主要目标是为训练有素的儿科胃肠病学家兼肝病学家Kohli博士提供途径，以实现科学独立性。通过使用小动物的手术 - 肥胖模型开发脂质和胆汁酸代谢方面的专业知识，他将使自己与导师兰迪·塞利（Randy Seeley）教授区分开来，并有充分的态度，以对儿童和青少年肥胖的理解做出重大的科学和医疗贡献。 公共卫生相关性：减肥手术现在已成为病态肥胖的成人或青少年的公认治疗方法。这些手术的某些好处，例如降低的胆固醇和糖尿病的分辨率，甚至在体重减轻之前也发生。该提案旨在确定这些与减肥液水平无关的关键机制，然后将这些发现转化为非侵入性更可扩展的治疗方案。