| Project/Area Number |
18590953
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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 |
Neurology
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| Research Institution | Kagoshima University |
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Principal Investigator |
HIGUCHI Itsuro Kagoshima University, Medical and Dental Hospital, Senior Assistant Professor (80183573)
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| Co-Investigator(Kenkyū-buntansha) |
TAKASHIMA Hiroshi Kagoshima University, Graduate School of Medical and Dental Sciences, Assistant Professor (80372803)
ARIMURA Kimiyoshi Kagoshima University, Graduate School of Medical and Dental Sciences, Associate Professor (20159510)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥3,850,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥450,000)
Fiscal Year 2007: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2006: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Keywords | Ullrich's disease / Bethlem mvonath / collagen VI / HSP47 / siRNA / extracellular matrix / ウールリッヒ病 / ベスレムミオパチー / トロンボモジュリン / Ullrich病(2)(3)(5)(6) / Collagen VI / NG2 proteolcan / collagen XV / collagen XVIII |
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| Research Abstract |
Collagenopathies with collagen VI mutations include Ullrich congenital muscular dystrophy (Ullrich's disease) and Bethlem myopathy. Patients with Ullrich's disease have generalized muscle weakness, multiple contractures of the proximal joints and hyperextensibility of the distal joints. Bethlem myopathy is characterized by the combination of proximal muscle weakness and contractures of finger, elbow, and ankle joints. We found for the first time a deficiency of collagen VI in Ullrich's disease. We found an overexpression of HSP47 in fibrous connective tissue and in the adjacent muscle membrane in various muscular dystrophies. However, in Ullrich congenital muscular dystrophy (UCMD), the overexpression of HSP47 was found only in the connective tissue, and not in the muscle membrane. Since the importance of basement membrane is well known during the regeneration of damaged skeletal muscle, the poor expression of HSP47 in the muscle basement membrane may also be related to the pathogenesis of Ullrich's disease. We show that siRNA-mediated knockdowns of hSMG-1 or hUPF1 cause up-regulation of the mutant triple helical collagen VI, resulting in the formation of partially functional extracellular matrix in Ullrich's disease. We conclude that the inhibition of nonsense-mediated mRNA decay (NMD) can be used as a therapeutic approach to rescue some human genetic diseases exacerbated by NMD.
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