Pathological analysis of GIST using transgenic or knock-in-mouse
| Project/Area Number |
13214058
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | HyogoColfege of Medicine (2004)
Osaka University (2001-2003) |
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Principal Investigator |
HIROTA Seiichi Hyogo College of Medicine, Faculty of Medicine, Professor, 医学部, 教授 (50218856)
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| Project Period (FY) |
2002 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥34,300,000 (Direct Cost: ¥34,300,000)
Fiscal Year 2004: ¥7,900,000 (Direct Cost: ¥7,900,000)
Fiscal Year 2003: ¥8,700,000 (Direct Cost: ¥8,700,000)
Fiscal Year 2002: ¥9,000,000 (Direct Cost: ¥9,000,000)
Fiscal Year 2001: ¥8,700,000 (Direct Cost: ¥8,700,000)
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| Keywords | 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 |
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| Research Abstract |
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.
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Report
(5 results)
Research Products
(30 results)
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[Journal Article] Endoscopic ultrasonography guided fine needle aspiration biopsy in follow-up patients with gastrointestinal stromal tumors.2003
Author(s)
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
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Journal Title
Eur J Gastroenterol Hepatol 15
Pages: 1189-1193
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Journal Article] C-kit gene mutation at exon 17 or 13 is very rare in sporadic gastrointestinal stromal tumors.2003
Author(s)
Kinoshita K, Isozaki K, Hirota S, Nishida T, Chen H, Nakahara M, Nagasawa Y, Ohashi A, Shinomura Y, Kitamura Y, Matsuzawa Y
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Journal Title
J Gastroenterol Hepatol. 18
Pages: 147-151
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Journal Article] Polyclonal nature of diffuse prolifera.tion of interstitial cells of Cajal in patients with familial and multiple gastrointestinal stromal tumours.2002
Author(s)
Chen H, Hirota S.Isozaki K, Sun H, Ohashi A, Kinoshita K, O'Brien P, Kapusta L, Dardick I, Obayashi T, Okazaki T, Shinomura Y, Matsuzawa Y, Kitamura Y
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Journal Title
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Journal Article] Familial gastrointestinial stromal tumors associated with dysphagia and novel type germline mutation of KIT gene.2002
Author(s)
Hirota, Nishida T, Isozaki K, Taniguchi M, Nishikawa K, Ohashi A, Takabayashi A, Obayashi T, Okuno T, Kinoshita K, Chen H, Shinomura Y, Kitamura Y
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Journal Title
Gastroenterology. 122
Pages: 1493-1499
Description
「研究成果報告書概要(欧文)」より
Related Report
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