Identification of susceptibility gene of diabetes mellitus by QTL analysis in the genetic modified mice

QTL分析鉴定转基因小鼠糖尿病易感基因

• 批准号: 13470227
• 负责人: ITAKURA Mitsuo
• 金额: $ 8.9万
• 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: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470227/
• 关键词: multifactorial disease; modifier gene for diabetes; type II diabetes; QTL analysis; db mice; susceptibility gene; animal model for diabetes; F2 intercross mice; コンジェニックマウス; スピードコンジェニック; サブ-コンジェニックマウス; 修飾遺伝子; ロッドスコア; 疾患病モデル動物

Diabetes is one of the typical "common diseases" and a major public health problem in Japan. Type 2 diabetes mellitus (T2D) results from the interaction between "genetic" and "environmental" factors. It is very important to identify the disease-susceptibility genes of diabetes. Mouse models of human diseases offer a powerful method to analyze human diseases. To identify the susceptibility genes of T2D, we performed genome-wide quantitative trait loci (QTL) analysis in 788 F_2 intercross generation between db mice carrying a mutation of leptin receptor (BKS-db/+m) with C3H/HeJ (C3H) mice. db mouse (BKS-db/db) having a mutation in the leptin receptor gene, is an animal model for T2D in humansThe phenotypes, including body weight, fasting blood glucose (BG) concentrations, fat weight, and intraperitoneal glucose tolerance test were determined. Correlation between genotypes with the whole genome 203 microsatellite markers and these quantitative phenotypes, were examined in a diabetic group including those homozygous for db (F_2-db/db) and a non-diabetic group including those heterozygous (F2 db/+m} and wild type (F_2-wild) for db. Vie found 18 QTLs (Lod Score >2.8 of suggestive value} for diabetes-related phenotypes including body weight, fat weight, and glucose tolerance. These loci also provide the susceptibility candidate regions to diabetes in humans. Production of the congenic mice is under way in our laboratory

糖尿病是日本典型的“常见病”之一，也是一大公共卫生问题。2型糖尿病(T2D)是遗传因素和环境因素相互作用的结果。识别糖尿病的易感基因是非常重要的。人类疾病的小鼠模型为分析人类疾病提供了一个强有力的方法。为了确定T2D的易感基因，我们对携带瘦素受体突变(BKS-db/+m)的db小鼠与C3H/Hej(C3H)小鼠杂交后的788个F2代进行了全基因组数量性状基因座(QTL)分析。具有瘦素受体基因突变的DB小鼠(BKS-db/db)是人类T2D的动物模型，测定了体重、空腹血糖(BG)浓度、脂肪重量和腹膜糖耐量试验等表型。对糖尿病组(包括db纯合子(F2-db/db))和非糖尿病组(包括杂合子(F2db/+m)和野生型(F2-Wildb))的全基因组203个微卫星标记与这些定量表型的相关性进行了研究。VIE发现了18个QTL(Lod Score&GT；2.8的提示值)，这些QTL与糖尿病相关的表型，包括体重、脂肪体重和葡萄糖耐量。这些基因座也提供了人类患糖尿病的候选区域。我们实验室正在进行同源基因小鼠的生产

项目成果

Takashi Yamaoka, et al.: "Feedback Inhibition of Amidophosphoribosyltransferase Regulates the Rate of Cell Growth via Purine Nucleotide, DNA, and Protein Syntheses."J.Biol.Chem.. 276(24). 21285-21291 (2001)

Takashi Yamaoka 等人：“酰胺磷酸核糖基转移酶的反馈抑制通过嘌呤核苷酸、DNA 和蛋白质合成调节细胞生长速率。”J.Biol.Chem. 276(24)。

Eiji Kudo, et al.: "Familial Juvenile Hyperuricemic Nephropathy : Detection of Mutation in the Uromodulin Gene in 5 Japanese Families"Kidney Int.. (in press). (2003)

Eiji Kudo 等人：“家族性青少年高尿酸血症肾病：5 个日本家族中尿调节蛋白基因突变的检测”Kidney Int..（出版中）。

Takashi Yamaoka: "Regenerative Therapy of Pancreatic β Cells toward a Cure for Diabetes"Biochem. Biophys. Res. Commun.. 296(5). 1039-1043 (2002)

Takashi Yamaoka：“胰腺 β 细胞再生疗法治疗糖尿病”Biochem.Res. 296(5)。

Masumi Nichi: "A Missense Mutant Myostatin Causes Hyperplasia without Hypertrophy in the Mouse Muscle"Biochem. Biophys. Res. Commun.. 293(1). 247-251 (2002)

Masumi Nichi：“错义突变体肌肉生长抑制素会导致小鼠肌肉增生而不肥大”Biochem。

Fujio Takeuchi: "HLA-DR Shared Epitope in Familial Cases of Japanese Rheumatiod Arthritis"Clin. Exp. Rheumatol.. 18. 424-426 (2001)

Fujio Takeuchi：“日本类风湿性关节炎家族病例中的 HLA-DR 共享表位”临床。