| Project/Area Number |
16K09373
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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 | Keio University |
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Principal Investigator |
Chu Po-sung 慶應義塾大学, 医学部(信濃町), 助教 (80570689)
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| Co-Investigator(Kenkyū-buntansha) |
尾城 啓輔 慶應義塾大学, 医学部(信濃町), 助教 (00383836)
海老沼 浩利 国際医療福祉大学, 医学部, 主任教授 (20296560)
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| Research Collaborator |
TAKIMOTO Youichi
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | 肝線維化 / マクロファージ / 自然免疫 / 免疫学 / 細胞・組織 / 内科 |
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| Outline of Final Research Achievements |
Liver cirrhosis, the end-stage of any chronic liver disease, is the leading cause of mortality and disability globally. By using murine liver fibrosis resolution models, we demonstrate that TLR4, which generally considered as pro-inflammatory and pro-fibrogenetic, also play a key role in fibrosis resolution, especially is mandatory for restorative macrophage induction through the TLR4-trem2 pathway. Through the gut-liver axis, TLR4 ligands needed for this process are provided. Subsequent liver regeneration are influenced by TGF-β/Foxp3+ Treg induced during fibrosis resolution. Our findings might provide critical insight to restorative macrophage induction as a novel anti-cirrhotic therapy in the future.
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| Academic Significance and Societal Importance of the Research Achievements |
全世界で肝硬変に関連する死亡者数は年間約200万人と推計される。肝疾患原因の排除だけでなく如何に肝線維化を消退させるのが重要な課題である。本研究は自然免疫応答を担うTLR4が肝線維化の消退期にも発現増加することから、TLR4における肝線維化の消退を制御するという未だに報告されていない新しい機序の存在を明らかにし、肝線維化を抑制する修復性マクロファージ(Restorative Macrophage)の誘導に自然免疫や腸肝関連の重要性を示唆した。「肝星細胞が肝線維化の中枢である」という昨今の規定概念を超え、修復性マクロファージ誘導を治療標的とする肝硬変の根本的な治療方法の開発に繋がると考えた。
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