IDENTIFICATION OF SUSCEPTIBILITY GENES FOR NIDDM

NIDDM 易感基因的鉴定

• 批准号: 2905597
• 负责人: Andrzej S Krolewski
• 金额: $ 33.81万
• 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/2905597
• 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《调查者摘要》)基因 易感性在非胰岛素的发生发展中起主要作用 依赖型糖尿病(NIDDM)。几个基因的参与 看起来很有可能，而且他们的身份识别已经变得可行 最近发展起来的分子遗传学方法。使用一大块面板 信息丰富的家庭，这项建议的目的是寻找 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，它们编码参与 肌肉中葡萄糖的处理以及新发现的基因 在NIDDM患者肌肉中高表达或低表达。具体目标 这项研究建议的是1)招聘和审查90名信息量大的 被选为最大限度提高检测能力的NIDDM患者家庭 NIDDM的易感基因；2)建立EBV转化的淋巴母细胞 为被检查的家庭成员(1200人)建立细胞系并准备 用于遗传学研究的DNA；3)NIDDM家族成员的基因分型 在四组候选基因上具有高度信息量的DNA标记 基因座：I)参与葡萄糖代谢和胰岛素作用途径的基因 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)中过度或低表达的基因 如RAD等NIDDM患者的肌肉和其他5-10名由 消减克隆；iii)已知的抑制胰岛素刺激的基因 葡萄糖摄取，如膜糖蛋白PC-1和肿瘤坏死因子-α；iv) β细胞中参与葡萄糖信号转导的基因，如：葡萄糖激酶和 电压依赖性钙通道的α-1亚基。4) 确定NIDDM与所检查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基因座上的等位基因变异有助于遗传病的发生。 NIDDM在一个重要的家庭子集。如果结果得到确认 在一个更大的家庭群体中，rad将是第一个与 NIDDM的发展。这些发现将为以下研究提供依据 特定分子缺陷的研究 对NIDDM的易感性。