| Project/Area Number |
12470143
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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 |
Neurology
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| Research Institution | Teikyo University |
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Principal Investigator |
SHIMIZU Teruo Teikyo University School of Medicine, Neurology, Professor, 医学部, 教授 (00107666)
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| Co-Investigator(Kenkyū-buntansha) |
SAITO Fumiaki Teikyo University School of Medicine, Neurology, Instructor, 助手 (40286993)
MATSUMURA Kiichiro Teikyo University School of Medicine, Neurology, Associate Professor, 助教授 (50260922)
小林 麻子 (長谷 麻子) 帝京大学, 医学部, 助手 (90328039)
山田 広樹 帝京大学, 医学部, 助手 (90260926)
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| Project Period (FY) |
2000 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥14,200,000 (Direct Cost: ¥14,200,000)
Fiscal Year 2003: ¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 2002: ¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 2001: ¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2000: ¥6,100,000 (Direct Cost: ¥6,100,000)
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| Keywords | α-dystroglycanopathy / dystroglycan / matrix metalloproteinase / extracellular matrix / cardiomyopathic hamster / sarcoglycanopathy / Fukuyama-type congenital muscular dystrophy / fukutin / 福山型先天性筋ジストロフィー / 筋ジストロフィー鶏 / 遠位型ミオパチー / 信号伝達 / 筋ジストロフィー / アポトーシス / dystrophin / caveolin-3 |
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| Research Abstract |
The dystroglycan (DG) complex, composed of two subunits αDG and βDG, interacts with the sarcoglycan complex to form the dystrophin-glycoprotein complex. αDG is a cell surface peripheral membrane protein which binds to the components of the extracellular matrix, while βDG is a type I integral membrane protein which anchors αDG to the cell membrane via the N-terminal extracellular domain. In this study, we have investigated the mechanisms by which the defects of the DG complex causes muscle cell dysfunction.
(1) We have characterized the matrix metalloproteinase (MMP) activity that disrupts the DG complex by cleaving the extracellular domain of βDG and found that this MMP is activated in the skeletal and cardiac muscles of cardiomyopathic hamsters, the model animal of sarcoglycanopathy. The results raise a therapeutic potential of the 'drugs that inhibit, this MMP activity to decelerate muscle degeneration in sarcoglycanopathy.
(2) In collaboration with Professor Tatsushi Toda (University of Osaka), we have developed and analyzed fukutin-deficient chimeric mice. These animals showed severe abnormalities of brain, eye and skeletal muscle, similar to FCMD. In the brain and skeletal muscle, glycosylation and laminin-binding of αDG were disturbed. These animals will be useful for further elucidation of FCMD pathogenesis.
(3) We have found that glycosylation and laminin-binding of αDG are disturbed in the brain and skeletal muscle of dystrophy chicken. These animals will be useful for further elucidation of pathogenesis of α-dystroglycanopathy.
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