| Project/Area Number |
14370236
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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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 | Senri-Kinran University (2003)
National Cardiovascular Center Research Institute (2002) |
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Principal Investigator |
SHIGEKAWA Munekazu Senri-Kinran University, Dept.of Human Life Sciences, Professor, 生活科学部, 教授 (00113738)
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| Co-Investigator(Kenkyū-buntansha) |
IWATA Yuko National Cardiovascular Center, Dept.of Molecular Physiology, Researcher, 循環分子生理部, 室員 (80171908)
DOI Junko Senri-Kinran University, Dept.of Human Life Sciences, Assistant Professor, 生活科学部, 講師 (50343728)
花田 裕典 国立循環器病センター研究所, 循環分子生理部, 室員 (60228509)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥8,200,000 (Direct Cost: ¥8,200,000)
Fiscal Year 2003: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2002: ¥4,200,000 (Direct Cost: ¥4,200,000)
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| Keywords | Dilated Cardiomyopathy / Muscular Dystrophy / Dystrophin-glycoprotein Complex / Muscle degeneration / Na+ / Ca2+ Exchanger / H+ Exchanger / 心不全 / 心筋症 / ジストロフィー / ストレッチ活性化チャネル / サルコグリカン |
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| Research Abstract |
Disruption of the dystrophin-glycoprotein complex(DGC) caused by genetic defects of dystrophin or sarcoglycans results in muscular dystrophy and/or cardiomyopathy in humans and animal models. However, the key early molecular events leading to myocyte degeneration remain elusive. In this study, we observed that the growth factor-regulated cation channel GRC, which belongs to the transient-receptor-potential(TRP) channel family, is elevated in the sarcolemma of skeletal and/or cardiac muscle in dystrophic human patients and animal models deficient in dystrophin or 5-sarcoglycan. However, total cell GRC does not differ markedly between normal and dystrophic muscles. Analysis of the properties of myotubes prepared from δ-sarcoglycan-deficient BIO14.6 hamsters revealed that GRC is activated in response to myocyte stretch and is responsible for enhanced Ca^<2+> influx and resultant cell damage as measured by creatine phosphokinase efflux. We found that cell stretch increases GRC translocation to the sarcolemma, which requires entry of external Ca^<2+>. Consistent with these findings, cardiac-specific expression of GRC in a transgenic mouse model produced cardiomyopathy due to Ca^<2+> overloading, with disease expression roughly parallel to sarcolemmal GRC levels. The results suggest that GRC is a key player in the pathogenesis of myocyte degeneration caused by DGC disruption. Besides these studies, we explored the regulatory mechanisms of Na^+/Ca^<2+> and Na^+/H^+ exchangers and their roles in the genesis of cardiac dysfunction.
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