IDENTIFICATION OF SUSCEPTIBILITY GENES FOR NIDDM

NIDDM 易感基因的鉴定

• 批准号: 2734147
• 负责人: Andrzej S Krolewski
• 金额: $ 32.51万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-02-27 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2734147
• 关键词: Epstein Barr virus; calcium channel; cell line; clinical research; diabetes mellitus genetics; family genetics; genetic markers; glucokinase; glucose metabolism; glycogen synthase; glycoproteins; hexokinase; hormone regulation /control mechanism; human subject; insulin; insulin receptor; linkage mapping; molecular cloning; muscle cells; noninsulin dependent diabetes mellitus; pancreatic islets; tumor necrosis factor alpha; voltage gated channel

DESCRIPTION: (Adapted from the Investigator's Abstract) Genetic susceptibility plays a major role in the development of non-insulin dependent diabetes mellitus (NIDDM). Involvement of several genes appears likely, and their identification has become feasible with recently developed methods of molecular genetics. Using a large panel of informative families, this proposal aims to find susceptibility genes for NIDDM using the candidate gene approach. The investigators will examine a series of known candidate genes which encode for proteins involved in glucose disposal in muscles as well as newly identified genes which are over- or under-expressed in muscles of NIDDM patients. The specific aims of this research proposal are to 1) Recruit and examine 90 informative families with NIDDM that have been selected to maximize power to detect susceptibility genes for NIDDM; 2) Establish EBV transformed lymphoblast cell lines for the examined family members (1200 individuals) and prepare DNA for genetic studies; 3) Genotype these members of the NIDDM families with highly informative DNA markers at four groups of candidate gene loci: I) Genes involved in glucose disposal and insulin action pathway such as: hexokinase II, glycogen synthase, insulin receptor, insulin receptor substrate-2; ii) Genes which are over- or under-expressed in muscle of patients with NIDDM such as rad and 5-10 others identified by subtraction cloning; iii) Genes known to inhibit insulin stimulated glucose uptake such as: membrane glycoprotein PC-1 and TNF-alpha; iv) Gene involved in glucose signaling in beta-cells such as: glucokinase and the alpha-1 subunit of the voltage-dependent calcium channels. 4) Determine linkage between NIDDM and the examined candidate genes using non-parametric and likelihood based methods. These investigators have obtained preliminary results which suggest that allelic variation at the rad locus contributes to the development of NIDDM in a significant subset of families. If the results are confirmed in a larger group of families, rad will be the first gene linked with the development of NIDDM. These findings will provide the bases for investigations of specific molecular defects which underlie susceptibility to NIDDM.

描述：（改编自研究者摘要）遗传 易感性在非胰岛素的发展中起着重要作用， 依赖性糖尿病（NIDDM）。涉及多个基因 似乎很可能，他们的身份已经成为可行的， 最近发展起来的分子遗传学方法。使用一个大的面板， 信息的家庭，这项建议的目的是找到易感基因， 使用候选基因方法的NIDDM。调查人员将检查 一系列已知的候选基因编码蛋白质， 葡萄糖在肌肉中的处理以及新发现的基因， 在NIDDM患者的肌肉中过度表达或表达不足。具体目标 本研究建议的主要内容是：1）招募和审查90名信息丰富的 选择NIDDM家族，以最大限度地提高检测能力 2）建立EBV转化的淋巴母细胞 检查家庭成员（1200人）的细胞系并准备 用于遗传研究的DNA; 3）对NIDDM家族的这些成员进行基因分型 在四组候选基因上具有高度信息性的DNA标记， 位点：I）参与葡萄糖处置和胰岛素作用途径的基因 例如：己糖激酶II、糖原合成酶、胰岛素受体、胰岛素 受体底物-2; ii）在细胞中过表达或低表达的基因， NIDDM患者的肌肉，如rad和5-10个其他人， iii）已知抑制胰岛素刺激的基因 葡萄糖摄取，例如：膜糖蛋白PC-1和TNF-α; iv） 参与β细胞中葡萄糖信号传导的基因，如：葡萄糖激酶和 电压依赖性钙通道的α-1亚单位。四、 确定NIDDM和检测的候选基因之间的连锁， 非参数和基于似然的方法。 这些调查人员已经获得了初步结果，表明， rad基因座的等位基因变异有助于 NIDDM在很大一部分家庭中存在。如果结果得到证实 在一个较大的家庭群体中，rad将是第一个与 NIDDM的发展。这些发现将为 研究了导致 易患NIDDM。