| Project/Area Number |
17K19888
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| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Health science and related fields
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| Research Institution | University of Tsukuba |
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Principal Investigator |
Suzuki Hideo 筑波大学, 医学医療系, 准教授 (00400672)
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| Co-Investigator(Kenkyū-buntansha) |
柳川 徹 筑波大学, 医学医療系, 教授 (10312852)
磯辺 智範 筑波大学, 医学医療系, 教授 (70383643)
蕨 栄治 筑波大学, 医学医療系, 講師 (70396612)
正田 純一 筑波大学, 医学医療系, 教授 (90241827)
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| Project Period (FY) |
2017-06-30 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2019: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | NASH / LPS / 遺伝子改変マウス / 遺伝子レスキューマウス / 腸管透過性 / 腸管透過 / 肥満 / 生活習慣病 / 脂肪性肝疾患 / 腸内細菌 / 炎症 / 酸化ストレス / 転写因子 / 脂肪性肝炎 / 腸内細菌叢 / エンドトキシン / 炎症応答 / 転写因子Nrf2 |
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| Outline of Final Research Achievements |
Sqstm1 and Nrf2-double knockout mice represent spontaneous onset of NASH. Using the mice, we elucidated the mechanism for Nrf2-assisted biological defense to prevent NASH onset and progression. In this year, we have newly developed intestine-specific Nrf2 gene rescue mice and analyzed alterations in phenotypes of the intestine, visceral fat, and liver.
In parallel with this study, we studied the effects of long-term oral administration of pH-insensitive redox nanoparticles (RNP) on NASH onset and progression. The administration of RNP significantly inhibited the progression of liver fibrosis in the NASH model. In the analysis of qPCR, the expression levels of inflammatory signaling molecules and fibrogenesis molecules were attenuated in the liver. It is suggested that RNP may be a promising drug for the treatment of NASH.
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| Academic Significance and Societal Importance of the Research Achievements |
NASHの発症には，腸内細菌叢の変化，腸管上皮透過性の変化，代謝性LPS血症，生体のLPSによる自然免疫の活性化により，肝の炎症病態が惹起される仮説が唱えられている．Nrf2が腸管において，また，どのような病態生理学的役割を演じているかは，病態医学と治療学の観点より重要な課題である．本研究の成果により，NASH発症病態の観点より，腸上皮におけるNrf2発現の重要性が解明出来る．また，マウスにNrf2賦活化剤を投与することで，NASH発症の抑止に繋がる，Nrf2活性化の重要性を解明することが出来る．今後のNASHの医療分野において，その予防・治療方法の進歩に向けて大きく前進すると考えられる．
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