| Project/Area Number |
21590932
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Yamaguchi University |
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Principal Investigator |
IKEDA Yasuhiro 山口大学, 大学院・医学系研究科, 助教 (00260349)
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| Co-Investigator(Kenkyū-buntansha) |
YANO Masafumi 山口大学, 医学部附属病院, 講師 (90294628)
YAMAMOTO Takeshi 山口大学, 大学院・医学系研究科, 助教 (50363122)
MATSUZAKI Masunori 山口大学, 大学院・医学系研究科, 教授 (60116754)
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| Research Collaborator |
宮崎 要介 山口大学, 大学院生
青山 英和 山口大学, 大学院生
白石 宏造 山口大学, 大学院生
西野 静香 山口大学, 技術補佐員
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| Project Period (FY) |
2009 – 2011
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| Project Status |
Completed (Fiscal Year 2011)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2011: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2010: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2009: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | protein phosphatase 1β / adeno-associated virus vector / gene therapy / RNAi / AAV9ベクター / protein phosphatase 1 beta / 心不全 / BNP / アデノ随伴ウイルスベクター / protein phosphatase 1 beta isoform / 筋小胞体 / カルシウム循環 / 心筋細胞 / Cカルシウム循環 / 心筋特異的ノックアウトマウス |
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| Research Abstract |
The targeting of Ca^<2+> cycling has emerged as a potential therapy for the treatment of severe heart failure. These approaches include gene therapy directed at overexpressing sarcoplasmic reticulum(SR) Ca^<2+> ATP_ase, or ablation of phospholamban(PLN) and associated protein phosphatase 1(PP1) protein complexes. We previously reported that PP1, one of the PP1 catalytic subunits, predominantly suppresses Ca^<2+> uptake in the SR among the three PP1 isoforms, thereby contributing to Ca^<2+> downregulation in failing hearts. In the present study, we investigated whether heart-failure-inducible PP1-inhibition by adeno-associated viral-9(AAV9) vector mediated gene therapy is beneficial for preventing disease progression in genetic cardiomyopathic mice. In the MLPKO mice, inducible PP1shRNA delivery preferentially ameliorated left ventricular diastolic function and mitigated adverse ventricular remodeling. Heart failure-inducible molecular targeting of PP1 has potential as a novel therapeutic strategy for heart failure.
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