| Project/Area Number |
16H03253
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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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| Research Field |
Applied health science
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| Research Institution | University of Tsukuba |
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Principal Investigator |
Nakagawa Yoshimi 筑波大学, 国際統合睡眠医科学研究機構, 准教授 (80361351)
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| Co-Investigator(Kenkyū-buntansha) |
島野 仁 筑波大学, 医学医療系, 教授 (20251241)
松坂 賢 筑波大学, 医学医療系, 教授 (70400679)
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| Project Period (FY) |
2016-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000)
Fiscal Year 2019: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2018: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2017: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2016: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
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| Keywords | 腸肝循環 / CREBH / SREBP / CRISPR/Cas9システム / 動脈硬化 / 非アルコール性脂肪肝 / 生活習慣病 / 肝がん / 慢性炎症 / 脂質代謝 / CRISPR/Cas9 / FGF21 / 遺伝子発現 / 脂質 / 糖尿病 / 栄養学 |
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| Outline of Final Research Achievements |
We clarified that the transcription factor CREBH could contribute to the therapeutic strategy of lifestyle-related diseases. CREBH-deficient mice developed high-fat diet-induced abnormal fatty liver, hepatitis, and small intestine structural abnormalities, and then exacerbated these diseases due to abnormal nutrition metabolism. Furthermore, we clarified that CREBH deficiency induces atherosclerosis and liver cancer, which are terminal images of lifestyle-related diseases. Furthermore, we newly generated tissue-specific CREBH overexpression / deficiency mice by creating genetically modified mice using the CRISPR / Cas9 system. Non-alcoholic fatty liver and arteriosclerosis were aggravated in even tissue-specific KO mice of the liver and small intestine. In this study, we clarified that CREBH plays a crucial role in the regulation of nutrient metabolism and nutrient absorption in the liver and small intestine, respectively, and is greatly involved in lifestyle-related diseases.
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| Academic Significance and Societal Importance of the Research Achievements |
CREBHは小胞体ストレスに応答し、炎症反応を惹起させるという報告があった。しかしながら、我々の研究からCREBHは実際には炎症を抑えるとともに、生活習慣病改善ホルモンFGF21を介し病態を改善させる新規の生活習慣病改善に寄与する転写因子であることを明らかにした。CREBHは脂質代謝の改善にも大きく関連し、すでに治療標的となっているPPARαの活性を制御することを見出している。CREBH KOマウスではPPARα活性化薬(フィブラート))による脂質代謝改善効果が失われる。フィブラートで治療できない脂質異常症の新たな治療標的としてCREBHで有効であることを示した。
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