2005 Fiscal Year Final Research Report Summary
Mechanism of heart failure in cardiomyopathy based on cytoskeletal abnormality
| Project/Area Number |
16590726
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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 | National Cardiovascular Center Research Institute |
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Principal Investigator |
IWATA Yuko National Cardiovascular Center Research Institute, Molecular Physiology, Senior Staff, 循環分子生理部, 室長 (80171908)
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| Project Period (FY) |
2004 – 2005
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| Keywords | cardiomyopathy / stretch activated channel / muscle degeneration / muscular dystrophy |
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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. Reduced sarcolemmal integrity in these models has been reported to result in altered calcium homeostasis. Previous studies have shown a correlative relationship between sarcolenmal localization of a GRC, growth factor-regulated cation channel in dystrophic muscle and muscle degeneration, but have not tested whether GRC activation precedes cell death or is a consecjuence of it. To test a casual relationship between GRC activation and muscle degeneration in dystrophin deficient mdx mice we introduced dominant negative GRC (DN-GRC) which has little activity in muscle. DN-GRC over expression on a C57/BL6 background produced no striking phenotype. DN-GRC transgenic (DN-GRC-Tg) mice crossed with mdx mice were tested for pathological indicators of necrosis, regeneration and membrane damage. These DN-GRC transgen containing mdx mice showed reduction in muscle necrosis and decrease in blood creatine kinase in 5-9 weeks of age. The extent of improvement correlated with the level of DNGRC protein expression in mdx. These data suggest that GRC play an active role in necrotic process in dystrophic muscle and that inhibition of GRC might provide a good therapeutic target for treatment of muscular dystrophy.
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