The Melanocortin-4 Receptor in Human Obesity

人类肥胖中的 Melanocortin-4 受体

• 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
• 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

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导致人类肥胖的基因突变，并了解它们对肥胖的影响。 致病作用 该建议集中在G蛋白偶联黑皮质素-4受体（MC 4 R）上，该基因在人黑色素瘤中表达。 中枢神经系统，并参与调节食物摄入。我们最初报告了第一个病例 人类肥胖与MC 4 R基因突变有关。在上一个融资周期，我们 广泛研究了MC 4 R突变在严重肥胖儿童和成人中的流行情况 人群;我们已经全面研究了超过50种不同的肥胖导致的功能缺陷， MC 4 R突变;我们进一步表征了MC 4 R突变携带者的表型，并已开始 研究这种疾病的基因型-表型关系。我们新的具体目标是： 1)扩展MC 4 R基因座在人类能量稳态中的作用的研究。我们将扩大我们的 通过测试MC 4 R基因座以外的遗传变异之间的关联，对整个MC 4 R基因座进行遗传研究。 MC 4 R的转录单位和最小启动子与肥胖相关的表型，在两个大的情况下- 对照研究和3，075个个体的良好表型多乙烯群组。我们将特别关注 我们在MC 4 R基因座进化保守区域的研究成果。 2)为了将肥胖成人MC 4 R突变携带者的基因型-表型关系的研究扩展到 减肥手术后的结果。一个主要的目标是确定基因的突变是负责 一个共同的人类肥胖是提供更合理的治疗方法，最终通过分层病人 分组，其中不同治疗的有效性可以根据经验确定。减肥手术 是目前治疗病态肥胖症最有效的方法。我们将使用一个大型前瞻性收集的队列 2400名接受减肥手术的患者，以确定MC 4 R突变携带者是否有不同的 结果是非运营商。我们还将系统地研究小说所造成的功能缺陷 在这个队列中检测到的突变，并测试减肥手术后的结果是否与肥胖相关。 MC 4 R突变携带者组内突变的功能特征。 3)研究黑皮质素-4受体组成性活性的分子机制 其N端结构域。通过系统研究肥胖相关的N-末端突变， 我们最近已经证明，该结构域保持MC 4 R的组成活性 并且这种组成活性是生理学相关的。我们将进一步确定其结构特征 通过其N-末端结构域促进受体的组成性激活。这些实验可以 导致新的策略来靶向MC 4 R用于治疗肥胖症。