Development of practically usefull Ws/Ws rat and its utilization

实用Ws/Ws大鼠的研制及其利用

• 批准号: 10558121
• 负责人: HIROTA Seiichi
• 金额: $ 8.32万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-10558121/
• 关键词: c-kit gene; mutant rats; Ws; intrapyloric pressure; fibrosis; memory; Wsラット; 中枢神経系; 海馬; c-kit レセプター; マスト細胞欠損ラット; マスト細胞; 突然変異ラット; 消化管ストローマ細胞腫; レセプターチロシンキナーゼ; カハール介在細胞; c-kit; 近交系ラット; 受容体チロシンキナーゼ

Ws/Ws rat is only the mutant of rat c-kit gene that we first found in the world in 1991. The c-kit gene encodes a receptor tyrosine kinase, KIT.And the ligand for KIT is stem cell factor, SCF.The KIT-SCF system is essential for development of mast cells and interstitial cell of Cajal(ICC). At present, brothers and sisters of rats that have Ws mutation are crossed each other through several generations in SLC Japan Co.Ltd.Ws/Ws rats will be stably available in near future.We carried out several investigations using Ws/Ws rats. First, the function of pyloric ring was examined by measuring intrapyloric pressure. In ICC-deficient Ws/Ws rats, the contraction pressure did not prolong as observed in +/+ rats, and spike-like waves were noted. The abnormal spike-like waves were considered to be a cause of bile reflux into stomach observed in Ws/Ws rats. Second, the role of mast cells in fibrosis was examined using mast cell-deficient Ws/Ws rats. In both lung and liver fibrosis models, fibrosis in Ws/Ws rats was more prominent than that in +/+ rats, suggesting that the increase of mast cells in fibrotic tissues is not a cause but a result of fibrosis. Third, we examined the role of KIT receptor in central nervous system by using Ws/Ws rats. Morris maze task revealed the impairment of spatial learning and the electrophysiological examination of hippocampal slice showed the impairment of synaptic potentiation in Ws/Ws rats.

WS/Ws大鼠是1991年在世界上首次发现的大鼠c-kit基因的突变体。C-KIT基因编码受体酪氨酸激酶KIT，KIT的配体是干细胞因子SCF。KIT-SCF系统对肥大细胞和Cajal间质细胞(ICC)的发育是必不可少的。目前，在SLC日本株式会社，Ws突变大鼠的兄弟姐妹经过几代杂交。Ws/Ws大鼠将在不久的将来稳定供应。我们利用Ws/Ws大鼠进行了几项研究。首先通过测量幽门内压来检测幽门环的功能。在ICC缺乏的Ws/Ws大鼠，收缩压不像+/+大鼠那样延长，并观察到棘波。异常棘波可能是Ws/Ws大鼠胆汁返流的原因之一。其次，利用肥大细胞缺陷Ws/Ws大鼠检测肥大细胞在纤维化中的作用。在肺和肝纤维化模型中，Ws/Ws大鼠的纤维化较+/+大鼠更为突出，提示纤维化组织中肥大细胞的增多不是纤维化的原因，而是纤维化的结果。第三，我们用Ws/Ws大鼠研究了KIT受体在中枢神经系统中的作用。Morris迷宫实验显示Ws/Ws大鼠空间学习障碍，海马片电生理检查显示Ws/Ws大鼠突触增强功能受损。

项目成果

Tsujimura Y,Kitamura Y et al.: "Activating mutation in the catalytic domain of c-kit elicts hematopoietic transformation"Blood. 93. 1319-1329 (1999)

Tsujimura Y、Kitamura Y 等人：“激活 c-kit 催化结构域中的突变引发造血转化”血液。

Hirota S,Kitamura Y,et al: "Gain-of-function mutations of c-kit in human gastro-intestinal stromal tumors" Sience. 279. 577-580 (1998)

Hirota S、Kitamura Y 等人：“人类胃肠道间质瘤中 c-kit 的功能获得突变”Sience。

Isozaki K, et al: "Germ-line activating mutation in the kinase domain of c-kit gene in familial gastrointestinal stromal tumors."Am J Pathol.. 157. 1581-1585 (2000)

Isozaki K 等人：“家族性胃肠道间质瘤中 c-kit 基因激酶结构域的种系激活突变。”Am J Pathol.. 157. 1581-1585 (2000)

Ito A,Kitamura Y et al.: "Inhibitory effect of transcription factor encoded by the mi allele in mast cells"Blood. 93. 1189-1196 (1999)

Ito A、Kitamura Y 等人：“肥大细胞中 mi 等位基因编码的转录因子的抑制作用”血液。

Nakama A, et al: "Disturbed pyloric motility in Ws/Ws mutant rats due to deficiency of c-kit-expressing intersititial cells of Cajal."Pathol Int.. 48. 843-849 (1998)

Nakama A 等人：“由于 Cajal 表达 c-kit 的间质细胞缺陷，导致 Ws/Ws 突变大鼠的幽门运动受到干扰。”Pathol Int.. 48. 843-849 (1998)