B3 RECEPTOR GENE MUTATION IN DIABETES PRONE MINORITIES

易患糖尿病的少数群体中的 B3 受体基因突变

• 批准号: 2458884
• 负责人: ALAN R. SHULDINER
• 金额: $ 16.29万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-01 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2458884
• 关键词: CHO cells; G protein; Mexican Americans; adenylate cyclase; beta adrenergic receptor; chemical association; clinical research; diabetes mellitus genetics; disease /disorder proneness /risk; enzyme activity; family genetics; gene mutation; genetic markers; genetic polymorphism; genotype; human subject; insulin sensitivity /resistance; intracellular transport; messenger RNA; mutant; noninsulin dependent diabetes mellitus; obesity; protein biosynthesis; receptor binding; receptor expression

DESCRIPTION (Adapted from Applicant's abstract): Central (visceral) obesity is a strong risk factor for insulin resistance and noninsulin dependent diabetes mellitus (NIDDM), as well as for hypertension, dyslipidemia, and accelerated atherosclerosis (the so-called insulin resistance syndrome). The investigators identified the first mutation in the beta3AR, a seven membrane spanning G protein-linked receptor that is expressed in visceral adipose tissue. In four distinct cohorts (Pima Indians, Finnish Caucasians, Japanese, and French Caucasians), this mutation is associated with decreased resting metabolic rate, and several features of the insulin resistance syndrome including central obesity, hyperinsulinemia, and increased blood pressure, as well as the accelerated (earlier) onset of NIDDM. This missense mutation (codon 64TGGTrp CGGArg; W64R) predicts a nonconservative change in the first intracellular loop, a region that is important for proper function. Indeed the investigators preliminary data suggest a marked defect of W64R beta3AR in activating adenylyl cyclase. The investigators hypothesize that this mutation results in decreased receptor expression and/or defective signalling in visceral adipose tissue. Altered function may cause a decrease in beta3AR-stimulated lipolysis and energy expenditure (thermogenesis), which in turn leads to preferential deposition of visceral fat (central obesity), and thus increased susceptibility to insulin resistance and NIDDM. The aims of this proposal are: 1) To determine the molecular mechanism(s) whereby this mutation increases genetic susceptibility to these disorders by expressing normal (wild type) and mutant W64R beta3AR in vitro, and studying receptor biosynthesis, intracellular trafficking, ligand binding, G protein association, and adenylyl cyclase activation; and 2) To define the importance of this mutation in Mexican Americans, a high risk minority population, by performing pedigree analysis in well-characterized subjects of the San Antonio Family Diabetes Study. These studies will (i) defie the molecular mechanism(s) whereby the W64R beta3AR mutation increases genetic susceptibility to obesity, insulin resistance and NIDDM; (ii) define the importance of this mutation in Mexican Americans; and (iii) provide important insights into the pathophysiology of these disorders as well as their treatment and prevention.

描述（改编自申请人的摘要）：中枢性（内脏）肥胖 是胰岛素抵抗和非胰岛素依赖性的一个强烈危险因素 糖尿病（NIDDM），以及高血压、血脂异常和 加速动脉粥样硬化（所谓的胰岛素抵抗综合征）。 研究人员发现了 beta3AR 中的第一个突变，即七种突变。 在内脏中表达的跨膜 G 蛋白连接受体 脂肪组织。 在四个不同的群体中（皮马印第安人、芬兰白种人、 日本人和法国白种人），这种突变与减少 静息代谢率和胰岛素抵抗的几个特征 包括向心性肥胖、高胰岛素血症和血液增多等综合征 压力，以及 NIDDM 的加速（早期）发作。 这 错义突变（密码子 64TGGTrp CGGArg；W64R）预测非保守突变 第一个细胞内环的变化，该区域对于 适当的功能。 事实上，研究人员的初步数据表明， W64R beta3AR 在激活腺苷酸环化酶方面的缺陷。 调查人员 假设这种突变导致受体表达减少 和/或内脏脂肪组织中的信号传导缺陷。 改变功能 可能会导致 beta3AR 刺激的脂肪分解和能量消耗减少 （生热作用），这反过来又导致内脏的优先沉积 脂肪（中心性肥胖），从而增加对胰岛素的敏感性 耐药性和 NIDDM。 本提案的目的是： 1) 确定 这种突变增加遗传性的分子机制 通过表达正常（野生型）和 体外突变体 W64R beta3AR，并研究受体生物合成， 细胞内运输、配体结合、G 蛋白缔合，以及 腺苷酸环化酶激活； 2) 定义这一点的重要性 墨西哥裔美国人（高风险少数群体）的突变 对桑人的特征明确的受试者进行谱系分析 安东尼奥家庭糖尿病研究。 这些研究将 (i) 挑战分子生物学 W64R beta3AR 突变增加遗传性的机制 对肥胖、胰岛素抵抗和 NIDDM 的易感性； (ii) 定义 这种突变在墨西哥裔美国人中的重要性； (iii) 提供 对这些疾病的病理生理学的重要见解以及 他们的治疗和预防。