| Project/Area Number |
18K15876
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 53020:Cardiology-related
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| Research Institution | International University of Health and Welfare (2020-2021)
Tohoku University (2018-2019) |
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Principal Investigator |
Shohei Ikeda 国際医療福祉大学, 医学部, 講師 (40808581)
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| Project Period (FY) |
2018-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | YAP / 心不全 / 圧負荷 / TEAD / OSM / 心筋脱分化 / 糖尿病性心筋症 / TEAD1 / Hippo / 糖尿病 / Yao |
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| Outline of Final Research Achievements |
In this study, I investigated the role of the Hippo deficiency and the persistent activation of YAP. Cardiac specific Hippo deficient mice showed the persistent activation of YAP in the heart. The mice showed the decrease of apoptosis and cell cycle re-entry related with YAP activation in the pressure-overload condition and finally showed severe heart failure. I found the mechanism was the cardiac dedifferentiation depended on the activation pathway of YAP-TEAD1-OSM. Furthermore I found the suppression of the pathway attenuated the heart failure. In addition, I found the cardiac activation of YAP in the model of diabetes. In the model, pressure overload induced severe heart failure accompanied cardiac dedifferentiation depended on the activation pathway of YAP-TEAD1-OSM.Finally, I found the cardiac dedifferentiation depended on the activation pathway of YAP-TEAD1-OSM in human diabetic cardiomyopathy.
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| Academic Significance and Societal Importance of the Research Achievements |
心臓でのYAPの活性化は生存維持や増殖活性を通じて、正に働くことが報告されるが、心臓のYAPの恒常活性化が心臓に与える影響が不明であった。今回の研究で心臓のYAPの恒常活性化が予想外に心不全増悪に働くことが分かった。機序としてYAP-TEAD1-OSM経路の活性化により心筋脱分化に起因する心不全が起こることが分かった。また同様の減少は糖尿病性心筋症でも起こることが分かった。今回の結果から心臓でのYAPの適正範囲の管理が心臓機能維持に重要であることが示唆されたこと、YAPの抑制が心機能保持・心不全治療に貢献する病態が存在することが示唆され、今後の循環器病に貢献しうる研究成果であったと考える。
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