2018 Fiscal Year Final Research Report
The role of aberrant mTOR activation in heart failure
| Project/Area Number |
16K09505
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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 |
Cardiovascular medicine
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| Research Institution | Sapporo Medical University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
丹野 雅也 札幌医科大学, 医学部, 准教授 (00398322)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Keywords | 心不全 / 分子心臓病学 / ネクロプトーシス / オートファジー / mTOR |
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| Outline of Final Research Achievements |
Significant roles of mTOR complex 1 (mTORC1) in heart failure have been shown in animal models of heart failure. However, contribution of mTORC1 to pathogenesis of human heart failure has not been characterized. By use of endomyocardial biopsy specimens, we found that mTORC1 activity was higher in patients with heart failure than in controls. Furthermore, autophagy in cardiomyocytes was impaired by activation of necroptotic signals via suppression of autolysosome formation. Inhibition of mTORC1 by rapamycin restored the autophagic flux in cardiomyocytes. The effect of rampamycin was mediated by novel inhibitory phosphorylation of RIP1 and led to cardiomyocyte protection from necroptosis. Taken together, the findings suggest that aberrant mTORC1 activation is a therapeutic target in heart failure.
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| Free Research Field |
循環器内科学
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| Academic Significance and Societal Importance of the Research Achievements |
mTORC1が恒常的に活性化する遺伝子疾患である結節性硬化症の腎腫瘍に対してmTORC1阻害薬は保険適応を取得している。申請者らは、非虚血性拡張型心筋症例において心筋mTORC1活性が顕著に亢進し、病理学的変化や予後と密接に関係していることを明らかにしており、mTORC1活性調節は心不全治療の新たな標的であると考えた。
オートファジー機能不全が心機能低下へ導く分子機構は不明なままである。本研究により解明されたオートファジーとネクローシスの直接的分子機構連関は新たな心不全治療法開発への足がかりになる。
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