| Project/Area Number |
20K08340
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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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| Review Section |
Basic Section 53010:Gastroenterology-related
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| Research Institution | Keio University |
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Principal Investigator |
Matano Mami 慶應義塾大学, 医学部(信濃町), 特任助教 (20439889)
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| Co-Investigator(Kenkyū-buntansha) |
南木 康作 慶應義塾大学, 医学部(信濃町), 助教 (30571137)
佐藤 俊朗 慶應義塾大学, 医学部(信濃町), 教授 (70365245)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | 胃がん / オルガノイド / エピゲノム / CRISPR-Cas9 |
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| Outline of Research at the Start |
本研究では，胃正常，腸上皮化生，悪性度の異なる多数の胃がんオルガノイドを作製し，エピゲノムプロファイルを取得することで，発がんおよび悪性化に寄与するエピゲノム変化の解明を目指す．またゲノム編集技術による機能解析や異種移植技術と組み合わせることで，生体内での分子遺伝学的異常と形質変化の因果関係を実証し，得られた知見をもとにHigh throughput 薬剤感受性試験によってエピゲノム異常という新しい観点に着目した標的治療の確立を目指す．
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| Outline of Final Research Achievements |
Recently, epigenetic mechanisms underlying gastric cancer development are highlighted. However, detailed molecular basis has not been fully elucidated. In this study, we aimed to reveal epigenetic mechanisms that contribute to malignant transformation and develop targeted therapies using organoid technology.
Comprehensive epigenetic analysis of a gastric cancer organoid library revealed that there is a subtype characterized by loss of activity of transcription factors characteristic of intestinal tracts and gain of activity of different types of transcription factors. This subtype had a particularly poor prognosis. To explore targeted therapies for this subtype, we conducted CRISPR-based knockout screening targeting epigenetic regulatory proteins. We are currently trying to identify proteins that can be targeted specifically to this subtype for therapeutic development.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究は，胃がんのエピゲノム異常という観点から新たな治療標的の可能性を探る研究である．胃がん発症・悪性化に関与する環境因子や分子遺伝学的変化を理解し，前がん病変を防ぐ予防医学や，がんの悪性化機構を阻害する新しい治療戦略の開発が期待される．
また本研究は，ヒト細胞を用いたエピゲノム異常による腫瘍進行の機序解明を図る技術基盤となりうるとともに，臨床疾患サンプルの純度，精度の高いエピジェネティクスデータとして，貴重なリソースとなり，臨床・研究・産業に与える影響は大きいと考えられる．
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