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Animal Experimentation system as an infrastructure to support translational progression of diabetes research to medical practice

动物实验系统作为支持糖尿病研究向医学实践转化的基础设施

基本信息

批准号：
17200029
负责人：
YOSUYUKI Ohnishi
金额：
$ 26.37万
依托单位：
Central Institute for Experimental Animals
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2007
项目状态：
已结题

项目摘要

The aim of this project is to establish an animal experimentation system expecting to progress translational research for type 2 diabetes disease. Type 2 diabetes considers as one of multiple risk factors for other lifestyle-related] diseases, and many factors influence for the disease such as genetic and environmental contribution. Therefore, we set up genetic background with strict congenic conditions. Knockout (KO) mice for IRS1 gene and IRS2 gene were bred into C57BU6 (B6) strain respectively. We also bred with 129 strains for those gene knockdown mice. The earlier onset of diabetic symptoms such as hyper blood glucose levels, intolerance in GTT (glucose tolerance test) and resistance in'Tr (insulin tolerant test) were observed in B6-IRS2 KO than original hybrid strain. B6-IRS2 KO mice caused diabetic in six weeks of age. There were any obvious phenotypic difference observed between mice delivered by natural mating and those by using in vitro fertilization and embryo transfer technology. B6-IRS2 KO mice were fed three types of foods containing with 5%, 10% and 15% of fat, respectively. Progression of the disease was observed on GTT in the group with 10% fat, and both on GTT and ITT in the 15% fat-feeding group. Clinical value of GTT was getting worse in 129-IRS2 KO mice than those of B6 background. On the other hand, 129-IRS2 KO mice showed relatively good response against insulin treatment.

本项目的目的是建立一个动物实验系统，以期在2型糖尿病疾病的转化研究中取得进展。2型糖尿病被认为是其他生活方式相关疾病的多重危险因素之一，许多因素如遗传和环境因素对该疾病的影响。因此，我们建立了具有严格遗传条件的遗传背景。将IRS1基因敲除（KO）小鼠和IRS2基因敲除（KO）小鼠分别培育到C57BU6 （B6）品系中。我们还培育了129株基因敲除小鼠。B6-IRS2 KO比原杂交品系更早出现糖尿病症状，如高血糖水平、GTT（葡萄糖耐量试验）不耐受和胰岛素耐量试验（胰岛素耐量试验）抵抗。B6-IRS2 KO小鼠在6周龄时引起糖尿病。自然交配法与体外受精和胚胎移植法生育的小鼠在表型上存在明显差异。B6-IRS2 KO小鼠分别饲喂脂肪含量为5%、10%和15%的三种食物。在脂肪摄取量为10%的组中观察到GTT的进展，在脂肪摄取量为15%的组中观察到GTT和ITT的进展。129-IRS2 KO小鼠GTT的临床价值明显低于B6背景小鼠。另一方面，129-IRS2 KO小鼠对胰岛素治疗表现出相对较好的应答。