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）：中央（内脏）肥胖 是胰岛素抵抗和非胰岛素依赖性的强大风险因素 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）。 调查人员确定了beta3ar中的第一个突变，七个 跨越内脏表达的G蛋白连接受体的膜 脂肪组织。 在四个不同的队列中（皮马印第安人，芬兰高加索人， 日语和法国高加索人），这种突变与减少有关 静息代谢率和胰岛素抵抗的几个特征 包括中枢肥胖，高胰岛素血症和血液增加的综合征 压力以及NIDDM的加速（早期）发作。 这 错义突变（密码子64TGGTRP CGGARG; W64R）预测一个非保守性 第一个细胞内环的变化，一个重要的区域 适当的功能。 确实，研究人员的初步数据表明了一个明显的 W64Rβ3AR的缺陷激活腺苷酸环化酶。 调查人员 假设这种突变导致受体表达降低 和/或内脏脂肪组织中的信号传导。 功能改变 可能导致β3AR刺激的脂解和能量消耗的减少 （热生成），进而导致内脏的优先沉积 脂肪（中央肥胖），因此增加了对胰岛素的敏感性 电阻和NIDDM。 该提案的目的是：1）确定 分子机制，该突变增加了遗传 通过表达正常（野生型）和 突变的W64R beta3ar体外，研究受体生物合成， 细胞内运输，配体结合，G蛋白关联和 腺苷酸环化酶激活； 2）定义这一点的重要性 墨西哥裔美国人的突变，高风险少数人口， 在SAN的良好特征主题中进行血统分析 安东尼奥家庭糖尿病研究。 这些研究将（i）违反分子 W64R beta3ar突变增加遗传的机制 对肥胖，胰岛素抵抗和NIDDM的敏感性； （ii）定义 在墨西哥裔美国人中这种突变的重要性； （iii）提供 对这些疾病的病理生理学以及 他们的治疗和预防。