| Project/Area Number |
15K09039
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
Uchino Koji 東京大学, 医学部附属病院, 助教 (00748725)
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| Co-Investigator(Kenkyū-buntansha) |
中川 勇人 東京大学, 医学部附属病院, その他 (00555609)
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| Project Period (FY) |
2015-04-01 – 2018-03-31
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| Project Status |
Completed (Fiscal Year 2017)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | 胆管癌 / IL-33 / オルガノイド / 胆管周囲付属腺 / マウスモデル / 肝外胆管癌 |
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| Outline of Final Research Achievements |
Based on the frequent mutations of Ras and TGFb pathways in ECC, we generated mice with tamoxifen-inducible duct cell-specific Kras activation and TGFbR2 deletion by crossing LSL-KrasG12D, Tgfbr2flox/flox, and K19CreER mice (KT-K19CreER). However, KT-K19CreER mice did not develop biliary tumors. Next, to analyze the additional effect of E-cadherin loss, KT-K19CreER mice were crossed with CDH1flox/flox mice (KTC-K19CreER). KTC-K19CreER mice developed invasive periductal infiltrating ECC within 4 weeks. Time-course analysis revealed that recombined biliary epithelial cells (BECs) lining the bile duct lumen died due to E-cadherin loss, whereas recombined cells could survive in the peribiliary glands (PBGs). Dying BECs released IL-33 and stimulated a regeneration by PBGs via type 2 innate lymphoid cells, eventually leading to ECC. Cell lineage tracing suggested PBGs as the cellular origin of ECC. This mouse model provides new insight into biliary injury-based ECC development.
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