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GPCR Variants as Genetic Determinants of Obesity

GPCR 变异作为肥胖的遗传决定因素

基本信息

批准号：
7249490
负责人：
ALAN S KOPIN
金额：
$ 75.88万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-15 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7249490
关键词：
Accounting Address American Appendix Body Composition Body Weight Body Weight Changes Body Weight decreased Body mass index Cell Line Childhood Clinical Clinical Data Code Combination Drug Therapy Confounding Factors (Epidemiology)Databases Development Disease Drug Delivery Systems Eating End Point Ensure Failure Frequencies G-Protein-Coupled Receptors General Population Genes Genetic Genetic Determinism Genetic Polymorphism Genetic Predisposition to Disease Genotype Haplotypes Health Campaign Heritability Human In Vitro Individual Intervention Laboratories Light Link Literature Medical Melanocortin 4 Receptor Methodology Morbid Obesity Mutation Non-Insulin-Dependent Diabetes Mellitus Numbers Obesity Population Population Study Predisposition Prevalence Protein Isoforms Proteins Public Health Qualifying Receptor Gene Recombinants Research Personnel Review Literature Rewards Role Screening procedure Series Subgroup Testing United States Variant Weight Weight Gain base cohort diabetic feeding gain of function gene environment interaction gene interaction genetic variant hedonic in vitro Assay in vivo insight lifestyle intervention link protein loss of function mutant novel obesity treatment programs receptor receptor function response

项目摘要

DESCRIPTION (provided by applicant): More than 26 percent of the U.S. population has a body mass index (BMI) in excess of 30 and thus qualifies as obese. Although heritability is a well-established factor in the development of obesity, the genes underlying this tendency have been difficult to identify. One of the few monogenic forms of obesity identified to date results from mutations GPCR, MC4R. In light of this precedent and the need to define more common explanations underlying genetic susceptibility to obesity, it is of particular note that pharmacologic and/or genetic evidence has implicated more than twenty GPCRs as modulators of food intake, body weight and/or the hedonic (i.e., rewarding) response to feeding. The vast majority of these receptors have multiple known non-synonymous (i.e., changes in coding sequence) variants. By analyzing the prevalence, pharmacologic function, and co-existence of GPCR polymorphisms in the Look AHEAD population we will test our central hypothesis that a significant portion of obesity in the general population is linked with abnormal GPCR function. We will first define the MC4R variants (known and novel) in the Look AHEAD population by sequence and haplotype analysis. Aim 1 will provide insight into the role of this receptor in a large cohort of obese diabetic subjects as well as address the controversy surrounding the extent to which a known common variant (VI031) is protective against obesity. In addition, study of the MC4R will establish a baseline on which to explore the importance of other factors (e.g., GPCR polymorphisms) as genetic determinants of body weight. Furthermore, the analysis of the MC4R will enable other Look AHEAD investigators to take this variable into account as a potentially confounding factor in defining clinical susceptibilities. In Aim 2, we will genotype non-synonymous coding region polymorphisms and haplotype markers in a series of twenty orexigenic, anorexigenic and hedonic GPCRs postulated to have an etiologic role in the development of obesity. These receptor variants have been identified from the NCBI SNP database and from the literature. In parallel, corresponding mutant recombinant GPCRs will be expressed in heterologous cell lines and pharmacologically assessed. Polymorphic receptors will be classified as gain of function, loss of function, or wild type. The correlation between functional abnormalities and phenotypic parameters will be assessed within the study population. In Aim 3, combinations of anorexigenic, orexigenic and hedonic receptor variants will be assessed as potential synergistic or additive factors underlying the polygenic basis of obesity and/or other Look AHEAD study endpoints.

描述（由申请人提供）：