| Project/Area Number |
16209026
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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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 |
MATSUZAKI Masunori Yamaguchi University, Graduate school of Medicine, Professor, 大学院医学系研究科, 教授 (60116754)
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| Co-Investigator(Kenkyū-buntansha) |
YANO Masafumi Yamaguchi University, Hospital, Assistant professor, 医学部附属病院, 講師 (90294628)
IKEDA Yasuhiro Yamaguchi University, School of Medicine, Research Associate, 医学部, 助手 (00260349)
AOKI Hiroki Yamaguchi University School of Medicine, School of Medicine, Associate Professor, 医学部, 助教授 (60322244)
KIMURA Yoshihiro Yamaguchi University, Graduate school of Medicine, Associate Professor, 大学院医学系研究科, 助教授 (90301308)
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| Project Period (FY) |
2004 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥43,420,000 (Direct Cost: ¥33,400,000、Indirect Cost: ¥10,020,000)
Fiscal Year 2006: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000)
Fiscal Year 2005: ¥10,920,000 (Direct Cost: ¥8,400,000、Indirect Cost: ¥2,520,000)
Fiscal Year 2004: ¥24,180,000 (Direct Cost: ¥18,600,000、Indirect Cost: ¥5,580,000)
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| Keywords | gene delivery / heart failure / sarcoplasmic reticulum / calcium handling / molecular therapy / 筋小胞体 / カルシウムイオン / 分子標的療法 / 慢性心不全 / 拡張型心筋症 / リアノジン受容体 / ドメイン相関 / 蛋白ホスファターゼ1 / 心筋症ハムスター / 高効率生体内遺伝子導入 / Inhibitor-2 / アデノウイルスベクター / アデノ随伴ウイルスベクター / 高効率生体内心筋遺伝子導入 / RyRドメインペプチド |
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| Research Abstract |
An abnormal regulation of intracellular Ca^<2+> by sarcoplasmic reticulum has been shown to be involved in the mechanism underlying contractile and relaxation dysfunction in heart failure. We investigated molecular targeting strategies of correcting the abnormal calcium regulation either via the ryanodine receptor (RyR) or via the SR calcium ATPase (SERCA) /phospholamban (PLN) complex in chronic heart failure. In RyR, we have found that a single amino acid mutation seen in the patient with arrhythmogenic right ventricular dysplasia can trigger abnormal domain interaction between amino-terminal and central peptide domain, leading to abnormal SR calcium leak and subsequent fetal arrhythmia. The same conformational change was observed in the failing heart, suggesting the similar arrhythmogenic mechanism. In addition, this kind of calcium leak is also triggered by the increased production of reactive oxygen species (ROS) in the failing heart. Therfore, reduction of ROS could be a novel str
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ategy to prevent fetal arrhythmia in heart failure Furthermore we also found that a classical medicine for malignant hyperthermia, dantrolene, can interfere with these abnormal conformational changes in RyR, thereby potentially correcting impaired calcium cycling in the failing heart.
On the other hand, calcium uptake function via SERCA pump and phospholamban in the network SR is also impaired in the failing heart. This has in part been attributed to the decreased levels of pholpholamban phosphorylation at Ser 16, possibly caused by the increased protein phosphatase 1 (PP1) activity in the failing heart. We have attempted to correct this abnormal increase in PP1 activity. Using in vivo high efficiency gene delivery technique, we have introduced an endogenous constitutive PP1 inhibitor, inhibitor-2, into the cardiomyopathic hamster heart. Inhibitor-2 gene delivery not only rescued the cardiac finction but also ameliorated BNP expression, cardiac fibrosis and extended the consequent survival time.
In summary, molecular targeting strategy in RyR or SERCA/PLN complex and associated PP1 could be a good therapeutic target for heart failure. Less
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