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Pathological analysis of GIST using transgenic or knock-in-mouse

使用转基因或敲入小鼠对 GIST 进行病理学分析

基本信息

批准号：
13214058
负责人：
HIROTA Seiichi
金额：
$ 21.95万
依托单位：
HyogoColfege of Medicine (2004)Osaka University (2001-2003)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13214058/
关键词：
GIST Familial and multiple GISTs model mouse knock-in-mouse Imatinib c-kit gene PDGFR alpha von Recklinghausen disease germline 機能獲得性突然変異マウスモデルトランスジェニックマウス germline mutation ICCs ジーンターゲティング

项目摘要

First, we tried to generate transgenic mice possessing c-kit gene mutation which was seen in patients with familial and multiple GISTs (gastrointestinal stromal tumors). Two types of transgenic mice was gained; one had juxtamembrane domain mutation and the other had tyrosine kinase n domain mutation. However, these mice showed neither hyperplasia of interstitial cells of Cajal (IGCs) nor multiple GISTs. We are generating knock-in-mouse as a more physiological model of human familial GISTs. The knock-in-mouse has c-kit gene mutation at tyrosine kinase II domain. We will investigate the knock-in-mouse in near future.During the above process, we examined the clonality of diffuse proliferation of ICCs in familial GIST patients. The proliferate lesion showed polyclonal nature while each GIST demonstrated to be monoclonal. We also showed that KIT activation by exon 17 mutation was not effectively inhibited by a selective tyrosine kinase inhibitor, Imatinib. The downstream molecules of KIT signal transduction were not also fully inhibited by Imatinib.We investigated the cause of GISTs without c-kit gene mutation. Approximately half of GISTs without c-kit gene mutation had PDGFR alpha gene mutation. Two types of PDGFR alpha gene mutation were seen, and the juxtamembrane domain mutation was effectively inhibited by Imatinib but the tyrosine kinase n domain mutation was not We demonstrated that regrowth of GISTs during the Imatinib treatment (development of resistant clone) was caused by an additional c-kit gene mutation to original c-kit gene mutatioa Moreover, we showed that GISTs from neuroflbromatosis type1 patients did not have any c-kit gene mutation.

首先，我们试图产生具有c-kit基因突变的转基因小鼠，该突变见于家族性和多发性GIST（胃肠道间质瘤）患者。获得了两种转基因小鼠，一种是膜结构域突变型，另一种是酪氨酸激酶n结构域突变型。然而，这些小鼠既没有表现出Cajal间质细胞（IGCs）的增生，也没有表现出多发性GIST。我们正在产生敲入小鼠作为人类家族性GIST的更生理模型。敲入小鼠在酪氨酸激酶II结构域具有c-kit基因突变。在此过程中，我们检测了家族性GIST患者ICC细胞弥漫性增殖的克隆性。增殖病变表现为多克隆性质，而每个GIST证明是单克隆的。我们还发现，选择性酪氨酸激酶抑制剂伊马替尼不能有效抑制外显子17突变引起的KIT激活。伊马替尼对KIT信号转导的下游分子也没有完全抑制作用。无c-kit基因突变的GIST中约有一半存在PDGFR α基因突变。伊马替尼能有效抑制PDGFR α基因的突变，但不能抑制酪氨酸激酶n结构域的突变。（抗性克隆的发展）是由原始c-kit基因突变的额外c-kit基因突变引起的。此外，我们发现来自1型神经纤维瘤病患者的GIST没有任何c-kit基因突变。