2002 Fiscal Year Final Research Report Summary
Molecular pathogenesis of peripheral dysmyelination common to laminin-2 deficient muscular dystrophy and leprosy
| Project/Area Number |
11470151
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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 |
MATSUMURA Kiichiro Teikyo University, Department of Neurology, Associate Professor, 医学部, 助教授 (50260922)
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| Co-Investigator(Kenkyū-buntansha) |
SAITO Fumiaki Teikyo University, Department of Neurology, Instructor, 医学部, 助手 (40286993)
HASE Asako Teikyo University, Department of Neurology, Instructor, 医学部, 助手 (90328039)
YAMADA Hiroki Teikyo University, Department of Neurology, Instructor, 医学部, 助手 (90260926)
MATSUMURA Kiichiro Teikyo University, Department of Neurology, Associate Professor (50260922)
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| Project Period (FY) |
1999 – 2002
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| Keywords | Myelination / Laminin-2 Deficiency / Leprosy / Laminin-2 / Dystroglycan / Schwann Cell |
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| Research Abstract |
Dysfunction of the dystroglycan (DG) complex is presumed to play a role in peripheral dysmyelination which is characteristically observed in both laminin-2 deficient congenital muscular dsytrophy and leprosy. In this study, we attempted to clarify its molecular pathogenesis and obtained the following results. (1) DG expression increased concomittant with the initiation of Schwann cell myelination in peripheral nerve. (2) DG expression decreased with degeneration and increased with regeneration of peripheral nerve. (3) A matrix metalloproteinase activity was identified that disrupts the link between the basal lamina and cell membrane via the DG complex by cleaving the extracellular domain of βDG. (4) A novel laminin-binding protein homologus to mammalian 30 kDa laminin-binding protein LBP30 was identified in the cell wall of Mycobacterium leprae and suspected to mediate host cell infection by the bacteria. (5) A transgenic mice with defects in the gene of caveolin-3 that functionally interacts with the DG complex was generated. The animals displayed a phenotype of severe muscular dsytrophy together with abnormal nNOS activity in muscle. (6) A 180 kDa extracellular matrix protein p180 was deficient in the muscle of Fukuyama type congential muscular dystrophy patients. In the nervous system, p180 was co-localized with the DG complex in the glia limitans basal lamina complex in brain and surrounding Schwall cell outer membrane in peripheral nerve. All together, these results indicate that dysfunction of the DG complex is involved in the molecular pathogenesis of nervous system defects such as peripheral dysmyelination and its modification may be effective as a therapy to correct these abnormalities.
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[Publications] Claudepierre, T., Dalloz, C., Mornet, D., Matsumura, K., Sahel, J. and Rendon, A.: "Characterization of the molecular architecture of the dystrophin associated glycoprotein complex in Muller glial cells"J. Cell Sci.. 113. 3409-3417 (2000)
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「研究成果報告書概要(欧文)」より
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[Publications] Masaki, T., Matsumurak, K., Hirata, A., Yamada, H., Hase, A.,Shimizu, T., Yorifuji, H., Motoyoshi, K. and Kamakura, K.: "Expression of dystroglycan complex in satellite cells of dorsal root ganglia"Acta Neuropathol.. 101. 174-178 (2001)
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[Publications] Sunada, Y., Ohi, H., Hase, A., Ohi, H., Hosono, T., Arata, S.,Higuchi, S., Matsumura, K. and Shimizu, T.: "Transgenic mice expressing mutant caveolin-3 show severe myopathy associated with increased nNOS activity"Hum. Molec. Genet.. 10. 173-178 (2001)
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「研究成果報告書概要(欧文)」より
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[Publications] Yamada, H, Saito, F., Fukuta-Ohi, H., Zhong, D., Hase, A., Arai, K., Okuyama, A., Maekawa, R., Shimizu, T. and Matsumura, K.: "Processing of β-dystroglycan by matrix metalldproteinase disrupts the link between the extracellular matrix and cell membrane via the dystroglycan complex"Hum. Molec. Genet.. 10. 1563-1569 (2001)
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「研究成果報告書概要(欧文)」より
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[Publications] Masaki, T., Matsumura, K., Hirata, A., Yamada, H., Hase, A., Arai, K., Shimizu, T., Yorifuji, H., Motoyoshi, K. and Kamakura, K.: "Expression of dystroglycan and the Iaminin-α2 chain in the rat peripheral nerve during development."Exp. Neurol. 174. 109-117, (2002)
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「研究成果報告書概要(欧文)」より
