The Melanocortin-4 Receptor in Human Obesity

人类肥胖中的 Melanocortin-4 受体

基本信息

批准号：
9068928
负责人：
CHRISTIAN VAISSE
金额：
$ 35.66万
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：
2002
资助国家：
美国
起止时间：
2002-02-15 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9068928
关键词：
Adult Biological Assay Brain Cause of Death Cilia Code Comparative Genomic Analysis Core Facility Coupled Cues Defect Disease Eating Enhancers Environment Eukaryotic Cell Exons Family Study Food Intake Regulation Funding GTP-Binding Proteins Gene Mutation Genes Genetic Predisposition to Disease Genomic Segment Genotype Grant Health Heritability Homeostasis Human Hypertension Indium Investigation Laboratories Lead Link Malignant Neoplasms Mediating Melanocortin 4 Receptor Melanocortin 4 receptor mutation Molecular Morbid Obesity Mus Mutation Myocardial Infarction Neuraxis Neurons Non-Insulin-Dependent Diabetes Mellitus Obesity Organelles Peripheral Phenotype Population Prevalence Study Public Health Regulation Regulatory Element Reporting Research Research Project Grants Research Proposals Risk Role Signal Transduction Site-Directed Mutagenesis Stroke Testing Twin Studies Untranslated RNA Variant Weight Zebrafish base cancer type insight mutation carrier neurotransmission new technology obesity in children obesity treatment receptor expression receptor function research study response transcription activator-like effector nucleases

项目摘要

DESCRIPTION (provided by applicant): Obesity leads to an increased risk for type 2 diabetes, heart attack, many types of cancer, hypertension, stroke, and is estimated to soon be the leading cause of death in the US. Through twin and family studies, obesity has been found to have a 40-70% heritability rate, pointing to a strong genetic etiology. The long-term objective of our research is to understand the cellular and molecular basis of long-term regulation of energy homeostasis in order to identify genes in which mutations cause obesity in humans and to discover new targets for the treatment of obesity. This research 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. Different mutations in the coding sequence of MC4R cause severe obesity in humans. In this proposal we will extend these previous findings by determining whether rare mutations in non-coding regulatory sequences of MC4R could be a cause of severe obesity. In addition, we have recently found that MC4R is expressed at the primary cilium, a cellular organelle that serves as a signaling hub for eukaryotic cells in general and neurons in particular. Another aim of our studies will be to determine the functional determinants of MC4R localization at the primary cilium as well as the effect of human-obesity associated mutations on this localization.

描述（由适用提供）：肥胖会导致2型糖尿病，心脏病发作，多种类型的癌症，高血压，中风的风险增加，据估计很快将成为美国的主要死亡原因。通过双胞胎和家庭研究，已经发现肥胖具有40-70％的遗传率，表明遗传病因强。我们研究的长期目标是了解能量稳态长期调节的细胞和分子基础，以鉴定突变导致人类肥胖并发现肥胖治疗的新靶标的基因。这项研究建议着重于G蛋白偶联的黑色素皮质素-4受体（MC4R），该基因在中枢神经系统中表达，并在食物摄入调节中实施。 MC4R编码序列的不同突变会导致人类严重的肥胖症。在此提案中，我们将通过确定MC4R的非编码调节序列中的罕见突变来扩展这些先前的发现可能是严重肥胖的原因。此外，我们最近发现，MC4R在原发性纤毛中表达，这是一种细胞细胞器，它是真核细胞的信号枢纽，尤其是神经元。我们研究的另一个目的是确定在原发性纤毛中MC4R定位的功能决定者，以及与人类肥胖相关突变对该定位的影响。