EXAMINATION OF OLETF-DERIVED Nidd QTLs BY CONSTRUCTION OF A SERIES OF CONGENIC STRAINS

通过构建一系列同源菌株来检查 OLETF 衍生的 Nidd QTL

• 批准号: 11480249
• 负责人: MATSUMOTO Kozo
• 金额: $ 9.22万
• 依托单位: The University of Tokushima
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11480249/
• 关键词: type 2 diabetes; obesity; OLETF; rat; QTL; congenic strain; Obesity; genome-wide; OLETF rat; loci; Congenic; F344; Diabetes; Rat; Genetics

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is one of the well-characterized animal models for the study of type II diabetes. Our previous QTL mapping identified 14 loci as candidates for the hyperglycemia in the OLETF rat. Here we generated a series of congenic animals by introgressing into normoglycemic F344 background all 14 OLETF-derived diabetic loci. Subsequent OGTT assay revealed that congenic strains for Nidd1, Nidd2, Nidd3 and Nidd10 showed significantly higher levels of blood glucose in comparison with parental host strain, F344. Furthermore, simultaneously made heterozygote animals for Nidd1, 2 and 10 were normoglycemia, indicating that these loci are recessively inherited. The other nine congenic strains were apparently normoglycemic presumably because the effect of a single locus is too small to be detected by the method employed here. These strains are currently raised on high-fat diet to see if dietary manipulation may help manifest genetic contribution of each locus more clearly. Furthermore, reverse congenic strains whereby F344-derived QTLs are introgressed into OLETF background are also under construction. We believe that these congenic strains should provide useful agents for decomposing complex diabetic traits and for subsequent positional cloning.

大冢Long-Evans德岛脂肪（OLETF）大鼠是研究II型糖尿病的良好表征的动物模型之一。我们先前的QTL定位确定了14个位点作为OLETF大鼠高血糖症的候选基因。在这里，我们通过将所有14个OLETF衍生的糖尿病基因座渗入血糖正常的F344背景中来产生一系列同类动物。随后的OGTT测定显示，与亲本宿主菌株F344相比，Nidd 1、Nidd 2、Nidd 3和Nidd 10的同源菌株显示出显著更高的血糖水平。此外，Nidd 1、2和10同时杂合子动物的遗传正常，表明这些位点是重复遗传的。其他9个同源菌株显然血糖正常，大概是因为一个单一的基因座的影响太小，无法检测的方法在这里。这些菌株目前在高脂肪饮食中饲养，以观察饮食操作是否有助于更清楚地显示每个基因座的遗传贡献。此外，F344来源的QTL渗入OLETF背景的反向同源株系也正在构建中。我们相信这些同类菌株应该为分解复杂的糖尿病特征和随后的定位克隆提供有用的试剂。

项目成果

Yamada et al.,and Matsumoto: "Identification of epistatic interactions involved in non-insulin-dependent diabetes mellitus in the Otsuka Long-Evans Tokushima"Exp.Animal. (In press).

Yamada 等人和 Matsumoto：“鉴定 Otsuka Long-Evans Tokushima 实验动物中涉及非胰岛素依赖性糖尿病的上位相互作用”。

Minami T.: "Role of Atp7b gene in spontaneous and N-diethylnitrosamine-induced carcinogenesis in a new congenic strain, WKAH.C-Atp7b rats"Jap. J. Cancer Res.. 92. 841-847 (2001)

Minami T.：“Atp7b 基因在新的同类品系 WKAH.C-Atp7b 大鼠自发性和 N-二乙基亚硝胺诱导的致癌作用中的作用”Jap。

Sugiura,et al.,and Matsumoto,K: "Identification of novel non-insulin-dependent diabetes mellitus susceptibility loci in the Otsuka Long-Evans Tokushima Fatty rat by MQM-mapping method"Mammalian Genome. 10. 1126-1131 (1999)

Sugiura 等人和 Matsumoto,K：“通过 MQM 作图方法鉴定大冢 Long-Evans 德岛脂肪大鼠中新型非胰岛素依赖性糖尿病易感基因座”哺乳动物基因组。

Moralejo D.J.: "Gepetic verification of the role of CCK-AR in pancreatic proliferation and blood glucose and insulin regulation using a congenic rat carrying CCK-AR null allele"Res. Com in Mol Patho Pharm.. (in press).

Moralejo D.J.：“使用携带 CCK-AR 无效等位基因的同源大鼠对 CCK-AR 在胰腺增殖、血糖和胰岛素调节中的作用进行基因学验证”Res。

Yamada,T.,et al.Matumoto,K.(分担): "Obesity and NIDDM : Lesson form the OLETF rat"ELSEVIER. 248(13〜26) (1999)

Yamada, T., et al. Matumoto, K.（合伙人）：“肥胖和 NIDDM：OLETF 大鼠的教训”ELSEVIER 248(13-26) (1999)