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，这些小鼠在家族性和多个GIST（胃肠道肿瘤）的患者中被发现。获得了两种类型的转基因小鼠。一个具有叶膜结构域突变，另一个具有酪氨酸激酶N结构域突变。但是，这些小鼠既没有表现出Cajal（IGC）的间质细胞的增生，也没有多个GIST。我们正在将媒体作为人类家族性格的更生理模型产生。敲门液在酪氨酸激酶II结构域中具有C-KIT基因突变。我们将在不久的将来调查途中的闸门。在上述过程中，我们检查了国际税患者中ICC弥漫性增殖的克隆性。增生的病变显示多克隆性质，而每一个要点都是单克隆的。我们还表明，外显子17突变激活的试剂盒不能被选择性酪氨酸激酶抑制剂伊马替尼有效抑制。伊马替尼也没有完全抑制Kit信号转导的下游分子。我们研究了没有C-KIT基因突变的GIST的原因。大约一半没有C-KIT基因突变的GIST具有PDGFRα基因突变。观察到两种类型的PDGFRα基因突变，伊马替尼有效地抑制了置膜结构域突变，但是酪氨酸激酶N结构域突变并不是我们并不是证明在imatinib治疗过程中的GIST在抗阻力治疗过程中是由额外的C-kit Gene Gene gene突变引起的，我们在imatinib治疗过程中会引起更多的c-Kit突变，从而引起了Gene gene突变。 1型神经知性病患者没有任何C-KIT基因突变。

项目成果

期刊论文数量（60）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Late resistance to imatinib therapy associated with a second KIT mutation in metastatic gastrointestinal stromal tumour.

伊马替尼治疗晚期耐药与转移性胃肠道间质瘤中的第二个 KIT 突变相关。

DOI：
发表时间：
2004
期刊：
Br J Cancer 90
影响因子：
0
作者：
Wakai T;Hirota S;et al.
通讯作者：
et al.

Hirota S: "Familial gastrointestinal stromal tumors associated with dysphagia and novel type germline mutation of KIT gene"Gastroenterology. 122. 1493-1499 (2002)

Hirota S：“与吞咽困难和 KIT 基因新型种系突变相关的家族性胃肠道间质瘤”胃肠病学。

DOI：
发表时间：
期刊：
影响因子：
0
作者：
通讯作者：

Chen H: "Imatinib inhibits various types of activating mutant KIT found in gastrointestinal stromal tumors."Int J Cancer. 105. 130-135 (2003)

Chen H：“伊马替尼抑制胃肠道间质瘤中发现的各种类型的激活突变 KIT。”Int J Cancer。

DOI：
发表时间：
期刊：
影响因子：
0
作者：
通讯作者：

Endoscopic ultrasonography guided fine needle aspiration biopsy in follow-up patients with gastrointestinal stromal tumors.

超声内镜引导下胃肠道间质瘤随访患者进行细针抽吸活检。

DOI：
发表时间：
2003
期刊：
Eur J Gastroenterol Hepatol 15
影响因子：
0
作者：
Kinoshita K;Isozaki K;Tsutsui S;Kitamura S;Hiraoka S;Watabe K;Nakahara M;Nagasawa Y;Kiyohara T;Miyazaki Y;Hirota S;Nishida T;Shinomura Y;Matsuzawa Y
通讯作者：
Matsuzawa Y

Nakahara M: "Dose-dependent and time-limited proliferation of cultured murine interstitial cells of cajal in response to stem cell factor"Life Sci. 70. 2367-2376 (2002)

Nakahara M：“培养的鼠卡哈尔间质细胞响应干细胞因子的剂量依赖性和时间限制的增殖”生命科学。