Molecular-Genetic Mechanisms for Early-Onset Obesity

早发性肥胖的分子遗传学机制

• 批准号: 6820274
• 负责人: EVGENY I ROGAEV
• 金额: $ 15.58万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6820274
• 关键词: bioenergetics; biological signal transduction; clinical research; disease /disorder onset; family genetics; gene environment interaction; gene mutation; genetic markers; genetic susceptibility; human subject; linkage mapping; metabolism disorder; molecular cloning; molecular pathology; nutrient intake activity; obesity; overeating; phenotype

DESCRIPTION (provided by applicant): Obesity in humans has reached epidemic proportions and is associated with numerous health risks, including cardiovascular disease, diabetes mellitus, certain types of cancer, and reproductive defects. Abnormal weight regulation is also linked to abnormal eating behaviors (bulimia nervosa and binge eating disorder, anorexia nervosa) and common psychiatric diseases. To elucidate the molecular mechanisms underlying extreme obesity and related phenotypes, we will study unique large families with a very early-onset form of obesity, associated with hyperphagia and metabolic dysfunction. We have recently described seven generation pedigrees with extremely obese children and adults in human genetic isolates. We plan to identify genes underlying obesity and to elucidate the molecular pathway leading to both physiological and behavioral pathogenesis in food intake. The specific aims are as follows: 1) the chromosomal locus and mutant genes will be isolated for monogenic severe obesity in families found in the genetic isolate; 2) pathogenic features of abnormal protein and downstream elements of the cascade pathway leading to excessive fat accumulation will be identified; 3) the interaction of these elements with other signal transduction systems underlying reproductive and metabolic pathogenesis will be elucidated. Positional cloning and mutation analysis will be used to accomplish these goals. Tissue samples from affected homozygous individuals and asymptomatic relatives will be collected to investigate the biological effect of the mutant gene and protein. The mechanisms of resistance to leptin receptor mediated signaling in the obese individuals will be elucidated by analysis of gene expression, and in vitro assays for intracellular signaling in a mammalian cell model. Because obesity is a frequent disorder with high risk of morbidity and mortality, identification of candidate genes and their products will help elucidate control mechanisms of food intake and body mass, and make possible the development of diagnostic markers and specific pharmacological interventions.

描述（由申请人提供）：人类肥胖已达到流行病的程度，并与许多健康风险相关，包括心血管疾病、糖尿病、某些类型的癌症和生殖缺陷。异常的体重调节也与异常的饮食行为（神经性贪食症和暴食症，神经性厌食症）和常见的精神疾病有关。为了阐明极端肥胖和相关表型的分子机制，我们将研究具有非常早发性肥胖的独特大家族，与摄食过多和代谢功能障碍相关。我们最近描述了在人类遗传隔离物中具有极度肥胖儿童和成人的七代系谱。我们计划找出肥胖的潜在基因，并阐明导致食物摄入的生理和行为发病机制的分子途径。具体目标如下：1）将在遗传分离物中发现的家族中分离单基因重度肥胖的染色体位点和突变基因; 2）将鉴定导致过度脂肪积累的级联途径的异常蛋白和下游元件的致病特征; 3）阐明这些元件与其他信号转导系统的相互作用，这些信号转导系统是生殖和代谢发病机制的基础。定位克隆和突变分析将用于实现这些目标。将从受影响的纯合子个体和无症状亲属中采集组织样本，以研究突变基因和蛋白质的生物学效应。肥胖个体中对瘦素受体介导的信号传导的抗性机制将通过基因表达分析和哺乳动物细胞模型中细胞内信号传导的体外测定来阐明。由于肥胖是一种常见的疾病，具有高发病率和死亡率的风险，候选基因及其产物的鉴定将有助于阐明食物摄入和体重的控制机制，并使诊断标志物和特异性药物干预的发展成为可能。