The Melanocortin-4 Receptor in Human Obesity

人类肥胖中的 Melanocortin-4 受体

基本信息

批准号：
8013384
负责人：
CHRISTIAN VAISSE
金额：
$ 9.84万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-22 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8013384
关键词：
Adult Case-Control Studies Characteristics Child Code Coupled Defect Disease Effectiveness Food Intake Regulation Funding GTP-Binding Proteins Gene Mutation Genes Genetic Genetic Predisposition to Disease Genetic Variation Genotype Goals Homeostasis Human Individual Lead Link Melanocortin 4 Receptor Melanocortin 4 receptor mutation Molecular Morbid Obesity Mutation N-terminal Neuraxis Obesity Outcome Patients Phenotype Population Predisposition Prevalence Study Promoter Regions Receptor Activation Reporting Research Personnel Role Testing Variant bariatric surgery cohort effective therapy mutation carrier novel obesity treatment promoter research study

Adult Case-Control Studies Characteristics Child Code Coupled Defect Disease Effectiveness Food Intake Regulation Funding GTP-Binding Proteins Gene Mutation Genes Genetic Genetic Predisposition to Disease Genetic Variation Genotype Goals Homeostasis Human Individual Lead Link Melanocortin 4 Receptor Melanocortin 4 receptor mutation Molecular Morbid Obesity Mutation N-terminal Neuraxis Obesity Outcome Patients Phenotype Population Predisposition Prevalence Study Promoter Regions Receptor Activation Reporting Research Personnel Role Testing Variant bariatric surgery cohort effective therapy mutation carrier novel obesity treatment promoter research study

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项目摘要

Our long-term objective is to identify gene mutations that cause obesity in humans and to understand their pathogenic effects. This proposal focuses on the G-protein coupled Melanocortin-4 Receptor (MC4R), a gene expressed in the central nervous system and implicated in the regulation of food intake. We had initially reported the first case of human obesity linked to a mutation in the gene encoding the MC4R. In the previous funding period we have extensively studied the prevalence of MC4R mutations in both severely obese children and adult populations; we have comprehensively studied the functional defects of over 50 different obesity causing MC4R mutations; we have further characterized the phenotype of MC4R mutation carriers and have started to study the genotype-phenotype relationship within this disease. Our new specific aims are: 1) To extend the study of the role of the MC4R locus in energy homeostasis in humans. We will extend our genetic studies to the entire MC4R locus by testing for an association between genetic variations outside of the transcriptional unit and minimal promoter of MC4R with obesity related phenotypes in both a large case- control study and a well phenotyped multi-ethinic cohort of 3,075 individuals. We will especially concentrate our efforts on evolutionary conserved regions at the MC4R locus. 2) To extend the study of the genotype-phenotype relationship in obese adult MC4R mutation carriers to the outcome after bariatric surgery. A major goal of identifying genes in which mutations are responsible for common human obesity is to provide more rational approaches to therapy, eventually by stratifying patients into groups in which the effectiveness of different treatments can be determined empirically. Bariatric surgery is currently the most effective therapy for morbid obesity. We will use a large prospectively collected cohort of 2400 patients undergoing bariatric surgery to determine if MC4R mutation carriers have a different outcome than non-carriers. We will also systematically study the functional defects caused by novel mutations detected in this cohort and test if the outcome after bariatric surgery can be correlated to the functional characteristics of the mutations within the group of MC4R mutation carriers. 3) To examine the molecular mechanisms involved in the constitutive activity of the melanocortin-4 receptor by its N-terminal Domain. Through the systematic study of obesity-associated mutations in the N-terminal domain of MC4R we have recently demonstrated that this domain maintains the constitutive activity of MC4R and that this constitutive activity is physiologically relevant. We will further identify the structural features contributing to the constitutive activation the receptor by its N-terminal domain. These experiments could lead to new strategies to pharmacologically target MC4R for the treatment of obesity.

我们的长期目标是确定引起人类肥胖的基因突变并理解其致病作用。该提案着重于G蛋白偶联的黑素皮质素-4受体（MC4R），该基因在该基因中表达中枢神经系统，与食物摄入的调节有关。我们最初报告了第一个案件与编码MC4R的基因突变有关的人类肥胖。在上一个资金期间我们已经广泛研究了严重肥胖儿童和成人的MC4R突变的患病率人口；我们已经全面研究了50多种不同肥胖的功能缺陷 MC4R突变；我们进一步表征了MC4R突变载体的表型，并且已经开始研究该疾病中的基因型 - 表型关系。我们的新特定目标是： 1）扩展了MC4R基因座在人类能量稳态中的作用的研究。我们将扩展我们的通过测试遗传变异以外的遗传变异之间的遗传研究在两个大病例中，具有与肥胖相关表型的MC4R的转录单元和最小启动子 - 对照研究和3,075个人的表型多乙二醇队列。我们将特别集中我们在MC4R基因座的进化保守区域上的努力。 2）将肥胖成人MC4R突变载体中基因型 - 表型关系的研究扩展到减肥手术后的结局。识别突变负责的基因的主要目标常见的人类肥胖是提供更合理的治疗方法，最终通过对患者进行分层分成可以从经验上确定不同治疗的有效性的组。减肥手术目前是病态肥胖症最有效的疗法。我们将使用大型前瞻性收集的队列在2400名接受减肥手术的患者中，确定MC4R突变载体是否具有不同结果比非携带者。我们还将系统地研究由新颖的功能缺陷在该队列中检测到的突变，并测试减肥手术后的结果是否可以与 MC4R突变载体组内突变的功能特征。 3）检查黑色皮质素-4受体的组成型活性涉及的分子机制通过其N末端域。通过对N末端中肥胖相关突变的系统研究 MC4R的域，我们最近证明了该域维持MC4R的本构活性并且这种构成活动在生理上是相关的。我们将进一步确定结构特征由其N末端结构域的受体有助于构成激活。这些实验可以导致新的策略将药理靶向MC4R治疗肥胖症。