Role of Pro-opiomelanocortin mutations in human obesity

阿片黑皮质素原突变在人类肥胖中的作用

• 批准号: 6986277
• 负责人: CHRISTIAN VAISSE
• 金额: $ 31.06万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6986277
• 关键词: clinical research; disease /disorder onset; family genetics; gene mutation; genetic polymorphism; genetically modified animals; hormone receptor; human subject; laboratory mouse; laboratory rat; neurons; nucleic acid sequence; nutrient intake activity; obesity; patient oriented research; phenotype; polymerase chain reaction; proopiomelanocortin; receptor expression; tissue /cell culture

DESCRIPTION (provided by applicant): Our long term objectives are to identify gene mutations that cause obesity in humans and to understand their pathogenic effects. We have previously demonstrated that mutations in the Melanocortin-4 receptor (MC4-R), a hypothalamus expressed gene implicated in the central regulation of food intake, cause a common form of obesity in humans. This research proposal focuses on the pro-opiomelanocortin (POMC) gene. This gene is expressed in the arcuate nucleus of the hypothalamus and encodes the physiologic agonist ligands of the MC4R. Homozygous null mutations in the POMC gene result in a rare form of obesity associated with adrenal insufficiency and alterations in hair pigmentation. Recent results in the literature as well as our preliminary findings suggest that heterozygous POMC mutations can predispose to common obesity. Our hypothesis is that a significant number of common severe obesity cases are due to such heterozygous mutations in the POMC gene. To investigate this hypothesis we propose the following specific aims: Aim 1) To determine the prevalence and association of rare POMC gene variants in severe and or early onset human obesity. We will evaluate the prevalence of rare POMC mutations in severe obesity by systematically screening cohorts of severely obese children and adults for mutations in the POMC coding sequence. We will verify the absence of such mutations in non-obese controls. We will analyze the segregation of obesity with the mutations in the families of the probands. We will search for specific phenotypes distinguishing obese POMC mutation carriers from other obese patients. Aim 2) To determine the in vitro effects of obesity associated POMC mutations. Starting with the known obesity-associated heterozygous mutations in the POMC gene, we will systematically evaluate the effects of all the obesity-associated POMC mutations. Specifically we will: 2.1- Examine the effects of human obesity associated POMC mutations on the processing of POMC. 2.2- Examine the effects of mutated human obesity associated POMC derived peptides on MC4R and MC3R activation. 2.3- Test for a toxic effect of human obesity associated POMC mutations on primary cultures of neurons. Aim 3) To determine the effects of obesity associated POMC mutations in vivo. To further confirm the pathogenicity of human obesity associated POMC mutations we will: 3.1- Evaluate the short term effects of mutated human obesity associated POMC derived peptides on food intake in rats. 3.2- Evaluate the long-term effects of transgenic over-expression of human obesity associated POMC mutations in mice. This work will be an additional step towards the genetic classification of obesity in humans and will contribute to the development of targeted preventive and therapeutic interventions based on the underlying genetic defects in the patients.

描述（由申请人提供）：我们的长期目标是鉴定导致人类肥胖的基因突变，并了解其致病作用。我们以前已经证明，黑皮质素-4受体（MC 4-R）的突变，下丘脑表达的基因参与食物摄入的中枢调节，导致人类肥胖的常见形式。这项研究计划的重点是pro-opiomelanocortin（POMC）基因。该基因在下丘脑的弓状核中表达，并编码MC 4 R的生理激动剂配体。POMC基因的纯合无效突变导致一种罕见的肥胖症，与肾上腺功能不全和毛发色素沉着改变有关。最近的文献结果以及我们的初步研究结果表明，杂合POMC突变可能易患普通肥胖症。我们的假设是，大量的常见严重肥胖病例是由于POMC基因中的这种杂合突变。为了研究这一假设，我们提出了以下具体目标：目的1）确定罕见的POMC基因变异体在严重和/或早发性人类肥胖中的患病率和关联。我们将通过系统筛查重度肥胖儿童和成人的POMC编码序列突变，评估重度肥胖中罕见POMC突变的患病率。我们将在非肥胖对照组中证实不存在此类突变。我们将分析肥胖与先证者家族中突变的分离。我们将寻找区分肥胖POMC突变携带者与其他肥胖患者的特定表型。目的2）研究肥胖相关POMC基因突变的体外效应。从已知的肥胖相关的POMC基因杂合突变开始，我们将系统地评估所有肥胖相关的POMC突变的影响。具体而言，我们将：2.1-检查人类肥胖相关的POMC突变对POMC加工的影响。2.2-检查突变的人肥胖相关POMC衍生肽对MC 4 R和MC 3R活化的影响。2.3-测试人类肥胖相关POMC突变对神经元原代培养物的毒性作用。目的3）研究肥胖相关的POMC基因突变在体内的作用。为了进一步证实人肥胖症相关POMC突变的致病性，我们将：3.1-评估突变的人肥胖症相关POMC衍生肽对大鼠食物摄入的短期影响。3.2-评价转基因过度表达人肥胖相关POMC突变对小鼠的长期影响。这项工作将是人类肥胖症遗传分类的又一步，并将有助于根据患者的潜在遗传缺陷制定有针对性的预防和治疗干预措施。