| Project/Area Number |
18K15908
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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 | National Center for Global Health and Medicine |
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Principal Investigator |
Soeda Kotaro 国立研究開発法人国立国際医療研究センター, その他部局等, 研究員(移行) (20748347)
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| Project Period (FY) |
2018-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | 心不全 / 糖尿病 / チロシンキナーゼ / Akt |
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| Outline of Final Research Achievements |
Because of development of diagnosis and treatments of coronary heart disease (CHD), the number of diabetes patients who die from CHD have decreased in recent years. However, the total number of diabetes patients who die from heart failure has not decreased yet in Japan. This epidemiology suggest some putative mechanisms of diabetic cardiomyopathy beyond inadequate perfusion by coronary artery stenosis. On the other hand, several research revealed that cardiomyocyte insulin resistance was found in diabetic model animals. Therefore, we ablated Akt in myocyte as an animal model of diabetic heart failure so that we found that muscle-specific Akt defecient mice exhibit severe heart failure with significant decreased mass of heart and mitochondrial dysfunction. Moreover, additive knock-down of TSC2 or FoxO1/4 ameliorated severity of heart dysfunction in vivo. These results suggest that cardiomyocyte Akt has a pivotal role in remaining normal heart function via TSC2 and FoxO1/4.
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| Academic Significance and Societal Importance of the Research Achievements |
従来から糖尿病には狭心症や心筋梗塞などの冠動脈疾患が合併することが知られていたが、それらの診療技術の進歩もあり、現在では大血管による血液灌流によらない糖尿病合併心不全の病態解明が求められている。また、古典的インスリン標的臓器のほかに心筋でもインスリン抵抗性が惹起されうることが明らかになっており、本研究ではインスリンシグナルの中心的伝達因子と考えられているAktとその下流に着目し、心不全発症との関連性を分子生物学的手法で明らかにした。このことは、心筋におけるFoxOやTSC2-mTORC1シグナルへの介入が同病態への治療となりうることを示唆している。
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