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Functional analysis of susceptibility genes for diabetes: gene-gene and gene-environment interaction

糖尿病易感基因的功能分析：基因-基因和基因-环境相互作用

基本信息

批准号：
16390264
负责人：
IKEGAMI Hiroshi
金额：
$ 8.96万
依托单位：
Kinki University (2006)Osaka University (2004-2005)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

项目摘要

To clarify genetic basis of diabetes mellitus for better understanding of molecular mechanisms of the disease pathogenesis and for the development of effective methods for prevention and intervention, molecular genetic studies on both type 1 and type 2 diabetes were performed in inbred animal models for type 1(NOD mice) and type 2 (NSY mice) diabetes, respectively with particular focus on gene-gene and gene-environmental interaction Analysis of consomic and congenic strains with NSY derived diabetogenic chromosomes introgressed onto control C3H/He genetic background revealed the existence of diabetogenic genes on mouse chromosome 11 and 14, respectively. Gene-gene interaction was demonstrated for obesity between chromosomes 11 and 14. Diabetogenic genes on both chromosomes 11 and 14 showed gene-environment interaction with markedly deteriorated phenotypes with supplementation of 30% sucrose in drinking water. Sub-congenic analysis demonstrated that diabetogenic genes on chromosome 11 consist of multiple components.Sub-congenic analysis of NOD mice congenic for Iddl6 region on chromosome 17 revealed that Iddl6 consists of multiple components and one of them is located in class I K region.Multi-center collaborative study team, termed the Japanese Study Group on Type 1 Diabetes Genetics was established and made it possible to perform large-scale genetic association studies with sufficient power on candidate genes for type 1 diabetes. Taking advantage of these valuable resources, contribution of INS, CTLA4, PTPN22 and SUMO4 on susceptibility to type 1 diabetes in Japanese was confirmed. The data generated from the present study provides valuable information on genetics of diabetes for future development of tailored medicine in the treatment of diabetes mellitus.

为了阐明糖尿病的遗传基础，更好地了解疾病发病机制的分子机制，并制定有效的预防和干预方法，我们分别在1型（NOD小鼠）和2型（NSY小鼠）糖尿病近交动物模型上进行了1型和2型糖尿病的分子遗传学研究，特别关注基因-基因和基因-环境相互作用分析。将 NSY 衍生的致糖尿病染色体渗入到对照 C3H/He 遗传背景上的同体和同源品系表明，小鼠 11 号和 14 号染色体上分别存在致糖尿病基因。 11 号和 14 号染色体之间的肥胖症存在基因-基因相互作用。在饮用水中添加 30% 蔗糖后，11 号和 14 号染色体上的糖尿病基因均显示出基因-环境相互作用，表型显着恶化。亚同源分析表明，11号染色体上的糖尿病基因由多个成分组成。对17号染色体Iddl6区域同源的NOD小鼠进行亚同源分析，发现Iddl6由多个成分组成，其中一个位于I类K区域。多中心协作研究小组，即日本1型糖尿病遗传学研究组的成立，使研究成为可能。对 1 型糖尿病的候选基因进行具有足够功效的大规模遗传关联研究。利用这些宝贵的资源，INS、CTLA4、PTPN22和SUMO4对日本人1型糖尿病易感性的贡献得到了证实。本研究产生的数据为未来开发治疗糖尿病的定制药物提供了有关糖尿病遗传学的宝贵信息。