| Project/Area Number |
14370212
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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 | Kawasaki Medical School |
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Principal Investigator |
SUNADA Yoshihide Kawasaki Medical School, Professor, 医学部, 教授 (00240713)
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| Co-Investigator(Kenkyū-buntansha) |
MURAKAMI Tatsuhumi Kawasaki Medical School, Associate Professor, 医学部, 助教授 (30330591)
HAGIWARA Hiroki Kawasaki Medical School, Assistant Professor, 医学部, 講師 (80276732)
NUKINA Nobuyuki RIKEN Brain Science Institute, Director, 脳科学総合研究センター・病因遺伝子研究グループ, ディレクター(研究職) (10134595)
GOTO Yuichi National Center for Neurology and psychiatry, Director, 神経研究所・疾病研究第2部, 部長(研究職) (20225668)
市川 弥生子 川崎医科大学, 医学部, 講師 (90341081)
大沢 裕 川崎医科大学, 医学部, 講師 (80246511)
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| Project Period (FY) |
2002 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥13,900,000 (Direct Cost: ¥13,900,000)
Fiscal Year 2004: ¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 2003: ¥5,400,000 (Direct Cost: ¥5,400,000)
Fiscal Year 2002: ¥5,800,000 (Direct Cost: ¥5,800,000)
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| Keywords | muscular dystrophy / caveolin-3 / nNOS / myostatin / signal transduction / トランスジェニックマウス / カベオリン / マイオスタチン / Smad2 / eNOS / 肥大型心筋症 / モデル動物 |
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| Research Abstract |
Caveolin is a cardinal component constituting caveola, flask shaped invagination of the plasma membrane and modulates signal transduction via bindings to various signaling molecules such as G-protein, NOS, c-Src, H-Ras, protein kinase C, etc. Caveolin-3 is predominantly expressed in skeletal muscle and is associated with the dystrophin-glycoprotein complex. Since the autosomal dominant limb-girdle muscular dystrophy caused by mutaions of the caveolin-3 gene was reported in 1998, our research has been focusing on a role of caveolin-3 in the pathogenesis of muscle degeneration in the context of signal transduction. Extensive analysis of transgenic mice carrying a caveolin-3 mutation disclosed that, (1)caveolin-3 is missing from the sarcolemma resulting from a dominant negative effect of the mutation, (2)increased nNOS activity is Involved in the pathogenesis, and (3)ER-stress induced apoptpsis may also result in muscle degeneration.
On the basis of these accumulated findings, we also examined a therapeutic potential of modulating signal transduction pathway related to muscle degeneration. We found that a down regulation of myostatin, a TGF-β superfamily molecule negatively regulating muscle volume, in the skeletal muscle from the mutant caveolin-3 transgenic mice. Since the prodomain of the myostatin precursor protein strongly inhibits the activity of the myostatin mature peptide, we hypothesized that blockade of myostatin activity by using the prodomain could improve muscular dystrophy phenotype of the mutant caveolin-3 transgenic mice. Introduction of the prodomain gene into the mutant caveolin-3 transgenic mouse skeletal muscle by genetic crossing completely reversed the myopathic phenotype. Our results indicated a promising therapeutic potential of myostatin blockade in the treatment of muscular dystrophy.
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