2021 Fiscal Year Final Research Report
Establishment of a novel mouse model that recapitulates human muscle invasive bladder cancer
| Project/Area Number |
19H03790
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 56030:Urology-related
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| Research Institution | Kyoto University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
小川 修 京都大学, 医学研究科, 名誉教授 (90260611)
吉野 喬之 京都大学, 医学研究科, 特定病院助教 (40734348)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Keywords | 浸潤性膀胱癌 / マウスモデル / 遺伝子改変マウス / CRISPR/Cas9 |
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| Outline of Final Research Achievements |
The useful animal models of bladder cancer that accurately recapitulate the human disease is lacking because the true driver genes and cell of origin is not well understood. From our previous results, we hypothesized that muscle invasive bladder cancer comes from Krt5 expressing urothelial cells and filtered driver gene candidates which are common in both human and mouse chemically induced bladder cancer model.
We demonstrated that bladder injection of adeno-associated virus with Pten and Kmt2c sgRNA into transgenic mice expressing Trp53 mutation and Cas9 protein specifically in Krt5 positive cells induces Pten and Kmt2c knockout in target cells using CRISPR/Cas9 system. As a result, we could confirm the carcinogenesis of bladder cancer in some mice.
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| Free Research Field |
膀胱癌
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| Academic Significance and Societal Importance of the Research Achievements |
今回の研究成果により、膀胱尿路上皮へのウイルスベクター感染効率の最適化を達成し、標的細胞特異的に遺伝子編集を誘導する実験系が確立された。少数ながら発癌を確認することができたが、現状では遺伝子編集効率が悪く、安定したマウスモデル樹立には至っていない。現在、オルガノイド技術を用いたより高確率で腫瘍形成するモデルの作成に取り組んでおり、一部の遺伝子型で腫瘍形成を確認している。今後、安定的に供給できる膀胱癌モデルが確立できれば、投薬実験を通じた薬剤耐性メカニズムの解明や新規薬剤の開発が期待される。
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