| Project/Area Number |
18K06929
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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 48040:Medical biochemistry-related
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| Research Institution | Hokkaido University (2019-2020)
Kyoto University (2018) |
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Principal Investigator |
Imajo Masamichi 北海道大学, 化学反応創成研究拠点, 特任准教授 (00633934)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | 腸上皮幹細胞 / オルガノイド / 環境刺激 / ERK MAP kinase / EGFR / ERK / Atoh1 / 分泌系細胞分化 / 感染応答 / ハイドロゲル / 腸上皮 / 組織幹細胞 / 環境応答 / オルガノイド培養 |
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| Outline of Final Research Achievements |
Functions of intestinal stem cells (ISCs) are modulated in response to environmental perturbations to maintain tissue homeostasis. In this study, we showed that changes in ERK MAP kinase activity dynamics regulate ISC responses to environmental stimuli. After infection with certain pathogens, Notch signaling inhibition promotes differentiation of ISCs into secretory lineages. We found that Notch signaling inhibition promotes pulse-like activation of ERK and induces expression of Atoh1, a master regulator of secretory differentiation, thereby promoting the differentiation. In addition, we also showed that ERK activity dynamics are changed during intestinal tumorigenesis, which underlies tumor-specific dependency on EGFR signaling. Our results indicate that ERK activity dynamics are dramatically changed depending on the intrinsic tissue status and the environmental stimuli, which plays a critical role in controlling ISC functions in both normal homeostasis and tumorigenesis.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究により、腸上皮幹細胞が腸内環境の変化に応じて機能を変化させ、組織恒常性を維持する機構の一端が明らかになった。特に、これまで細胞増殖に中心的な役割を果たすと考えられていたERKが幹細胞の分化方向の制御にも重要な役割を果たすことを示した。また、ERKの活性化状態の変化が腸腫瘍特異的な性質にも関与していることが明らかになった。これらの研究成果の背景には、最新の生体イメージング法によりERKの活性を生きたマウス組織やオルガノイド内で経時的に単一細胞レベルで観察可能になったことがある。この技術は他の組織や分子にも応用可能であり、今後の組織幹細胞研究においてますます重要な手法になると期待される。
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