Role of brain insulin in the regulation of branched-chain amino acid metabolism

脑胰岛素在支链氨基酸代谢调节中的作用

• 批准号: 9063544
• 负责人: Andrew Changhun Shin
• 金额: $ 5.08万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9063544
• 关键词: Acute; Affect; Amino Acids; Biological Assay; Brain; Branched-Chain Amino Acids; Catabolism; Communication; Data; Development; Diabetes Mellitus; Energy Metabolism; Environment; Enzymes; Euglycemic Clamping; FRAP1 gene; Future; Gastric Bypass; Genetic; Glucose; Glucose Clamp; Goals; Health; Hepatic; Homeostasis; Hypothalamic structure; Immunoblotting; Individual; Infusion procedures; Insulin; Insulin Receptor; Insulin Resistance; Keto Acids; Knowledge; Light; Lipids; Literature; Liver; Medicine; Mentors; Mentorship; Metabolic; Metabolic syndrome; Metabolism; Modeling; Neurons; Neurosecretory Systems; Obesity; Operative Surgical Procedures; Organ; Oxidoreductase; Pancreas; Pathway interactions; Peripheral; Pharmacological Treatment; Physiological; Plasma; Play; Preventive measure; Procedures; Rattus; Regulation; Research; Research Personnel; Resources; Role; Supplementation; Testing; Training; Training Programs; Universities; Up-Regulation; Work; amino acid metabolism; authority; bariatric surgery; base; career; combat; design; diabetic; fighting; improved; instrumentation; insulin signaling; loss of function; medical schools; metabolomics; novel; programs; research study; skills; tool

DESCRIPTION (provided by applicant): The proposed research describes a mentored training program in neuroendocrine regulation of metabolism, designed to provide the candidate the necessary skills and resources that will allow him to achieve the long- term goal of developing a career as an independent neurobiologist at a research-oriented university. Department of Medicine at Mount Sinai School of Medicine has well-established programs with state-of-the-art analytical instrumentations. The primary mentor, Dr. Christoph Buettner, is an established investigator and is well respected in the field of energy metabolism, while the co-mentors are authorities in metabolomics, gut- brain communication and bariatric surgery, and metabolic syndrome. The abundant institutional resources and excellent mentorship from these experts will provide an ideal training environment for the candidate to develop independence. The research plan focuses on central insulin action and its role in the regulation of branched- chain amino acid (BCAA) metabolism. Combining physiological and metabolic targeting tools with genetic, pharmacological, and surgical approaches, the experiments described in the proposal will identify: (1) the role of hypothalamic insulin on circulating BCAAs and their intermediates; () hepatic BCAA catabolism as controlled by the central insulin action; and (3) systemic and liver BCAA metabolism affected by Roux-en-Y gastric bypass (RYGB) surgery, and the potential role of central insulin action after RYGB. The proposed studies will advance our understanding of BCAA homeostasis that is under the control of hypothalamic insulin, and explain how this is perturbed in obesity and diabetes. Importantly, identifying central insulin action as a mechanism through which RYGB successfully improves BCAA metabolism holds promise for future development of non-invasive pharmacological treatments that mimic the surgery-induced effects.

描述（由申请人提供）：拟议的研究描述了代谢神经内分泌调节方面的指导培训计划，旨在为候选人提供必要的技能和资源，使他能够实现在研究型大学发展成为独立神经生物学家的职业的长期目标。西奈山医学院医学系拥有完善的课程和最先进的分析仪器。主要导师 Christoph Buettner 博士是一位知名研究者，在能量代谢领域备受尊敬，而共同导师则是代谢组学、肠脑通讯、减肥手术以及代谢综合征领域的权威。丰富的机构资源和专家的优秀指导将为候选人发展独立性提供理想的培训环境。该研究计划重点关注胰岛素的中枢作用及其在支链氨基酸（BCAA）代谢调节中的作用。该提案中描述的实验将生理和代谢靶向工具与遗传、药理学和手术方法相结合，将确定：（1）下丘脑胰岛素对循环支链氨基酸及其中间体的作用； () 肝脏 BCAA 分解代谢受中枢胰岛素作用控制； (3) Roux-en-Y 胃绕道手术 (RYGB) 手术对全身和肝脏 BCAA 代谢的影响，以及 RYGB 后中枢胰岛素作用的潜在作用。拟议的研究将增进我们对下丘脑胰岛素控制下的 BCAA 体内平衡的理解，并解释肥胖和糖尿病中这种平衡是如何受到干扰的。重要的是，将中枢胰岛素作用确定为 RYGB 成功改善 BCAA 代谢的机制，有望为未来开发模仿手术引起的效果的非侵入性药物治疗带来希望。