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: 7122522
• 负责人: CHRISTIAN VAISSE
• 金额: $ 30.33万
• 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/7122522
• 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）：我们的长期目标是确定引起人类肥胖症并理解其致病作用的基因突变。我们以前已经证明，黑色素皮质素-4受体（MC4-R）中的突变是一种与食物摄入中心调节有关的基因的下丘脑，引起人类肥胖的常见形式。这项研究建议着重于蛋白聚糖素（POMC）基因。该基因在下丘脑的弧形核中表达，并编码MC4R的生理激动剂配体。 POMC基因中的纯合无效突变会导致一种与肾上腺功能不全和毛发色素沉着变化有关的罕见肥胖形式。文献以及我们的初步发现的最新结果表明，杂合POMC突变可能易感性肥胖。我们的假设是，大量常见的严重肥胖病例是由于POMC基因中的这种杂合突变引起的。为了研究这一假设，我们提出了以下特定目的：目的1）确定罕见的POMC基因变体在严重和或或或或或早期发作的人类肥胖症中的患病率和关联。我们将通过系统地筛选严重肥胖的儿童和成人的同类群体中的POMC编码序列中的突变来评估严重肥胖症中罕见的POMC突变的患病率。我们将验证非肥胖对照中缺乏此类突变。我们将通过概率家族中的突变分析肥胖的分离。我们将搜索区分肥胖POMC突变携带者和其他肥胖患者的特定表型。目标2）确定肥胖相关的POMC突变的体外作用。从POMC基因中的已知肥胖相关杂合突变开始，我们将系统地评估所有与肥胖相关的POMC突变的作用。具体而言，我们将：2.1-检查与人类肥胖相关的POMC突变对POMC加工的影响。 2.2-检查突变的人肥胖相关的POMC衍生肽对MC4R和MC3R激活的影响。 2.3-对人肥胖相关的POMC突变对神经元原发性培养的毒性作用的测试。目标3）确定体内肥胖相关的POMC突变的影响。为了进一步确认与人类肥胖相关的POMC突变的致病性：3.1-评估突变的人肥胖相关POMC衍生肽对大鼠食物摄入的短期影响。 3.2-评估小鼠与人肥胖相关的POMC突变的转基因过表达的长期影响。这项工作将是朝着人类肥胖的遗传分类的额外一步，并将有助于基于患者潜在的遗传缺陷的有针对性的预防和治疗干预措施的发展。