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2003 Fiscal Year Final Research Report Summary

Musecle cell dysfunction caused by disturbed cell adhesion and signal transduction

Research Project

Project/Area Number 12470143
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Neurology
Research InstitutionTeikyo University

Principal Investigator

SHIMIZU Teruo  Teikyo University School of Medicine, Neurology, Professor, 医学部, 教授 (00107666)

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)
Project Period (FY) 2000 – 2003
Keywordsα-dystroglycanopathy / dystroglycan / matrix metalloproteinase / extracellular matrix / cardiomyopathic hamster / sarcoglycanopathy / Fukuyama-type congenital muscular dystrophy / fukutin
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.

  • Research Products

    (23 results)

All Other

All Publications (23 results)

  • [Publications] Sunada, Y., et al.: "Transgenic mice expressing mutant caveolin-3 show severe myopathy associated with increased nNOS activity."Hum.Molec.Genet.. 10. 173-178 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yamada, H., et al.: "Processing of β-dystroglycan by matrix metalloproteinase disrupts the link between the extracellular matrix and cell membrane via the dystroglycan complex."Hum.Molec.Genet.. 10. 1563-1569 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Sunada, Y., et al.: "Deficiency of a 180-kDa extracellular matrix protein in Fukuyama type congenital muscular dystrophy skeletal muscle."Neuromusc.Disord.. 12. 117-120 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Takeda, S., et al.: "Fukutin is required for maintenance of muscle integrity, cortical histiogenesis, and normal eye development."Hum.Molec.Genet.. 12. 1449-1459 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Matsumura, K., et al.: "Disruption of dystroglycan axis by β-dystroglycan processing in cardiomyopathic hamster muscle."Neuromusc.Disord.. 13. 796-803 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Saito, F., et al.: "A Japanese patient with distal myopathy with rimmed vacuoles : Missense mutations in the epimerase domain of the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinsse gene accompanied by hyposialylation of skeletal muscle glycoproteins."Neuromusc.Disord.. 14. 158-161 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Masaki, T., Matsumurak, K., Hirata, A., Yamada, H., Hase, A., Shimizu, T., Yorifuji, H., Motoyoshi, K., Kamakura, K.: "Expression of dystroglycan complex in satellite cells of dorsal root ganglia"Acta Neuropathol.. 99. 289-295 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Claudepierre, T., Dalloz, C., Mornet, D., Matsumura, K., Sahel, J., Rendori, A.: "Characterization of the molecular architecture of the dystrophin associated glycoprotein complex in Muller glial cells"J. Cell Sci.. 113. 3409-3417 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Masaki, T., Matsumurak, K., Hirata, A., Yamada, H., Hase, A., Shimizu, T., Yorifuji, H., Motoyoshi, K., Kamakura, K.: "Expression of dystroglycan complex in satellite cells of dorsal root ganglia"Acta Neuropathol.. 101. 174-178 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Sunada, Y., Ohi, H., Hase, A., Ohi, H., Hosono, T., Arata, S., Higuchi, S., Matsumura, K., Shimizu, T.: "Transgenic mice expressing mutant caveolin-3 show severe myopathy associated with increased nNOS activity"Hum. Molec. Genet.. 10. 173-178 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yamada, H., Saito, F., Fukuta-Ohi, H., Zhong, D., Hase, A., Arai, K., Okuyama, A., Maekawa, R., Shimizu, T., Matsumura, K.: "Processing of β-dystroglycan by matrix metalloproteinase disrupts the link between the extracellular matrix and cell membrane via the dystroglycan complex"Hum. Molec. Genet. 10. 1563-1569 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kaminaga, T., Matsumura, K., Hatanaka, Y., Shimizu, T.: "Abnormality of the myocardial sympathetic nervous system in a patient with Becker muscular dystrophy detected with Iodine-123 metaiodobenzylguanidine scintigraphy"Clin. Nuci. Med.. 26. 701-703 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Sunada, Y., Ohsawa, Y., Murakami, T., Matsumura, K., Shimizu, T.: "Caveolin-3 and muscular dystrophy"Acta Myologica. 20. 162-167 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Sunada, Y., Saito, F., Higuchi, I., Matsumura, K., Shimizu, T.: "Deficiency of a 180-kDa extracellular matrix protein in Fukuyama type congenital muscular dystrophy skeletal muscle"Neuromusc. Disord.. 12. 117-120 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Masaki, T., Matsumura, K., Hirata, A., Yamada, H., Hase, A., Arai, K., Shimizu, I., Yorifuji, H., Motoyoshi, K., Kamakura, K.: "Expression of dystroglycan and the laminin-α2 chain in the rat peripheral nerve during development"Ex Neurol.. 174. 109-117 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Takeda, S., Kondo, M., Sasaki, J., Kurahashi, H., Kano, H., Arai, K., Misaki, K., Fukui, T., Kobayashi, K., Tachikawa, M., Imamura, M., Nakamura, Y., Shimizu, T., Murakami, T., Sunada, Y., Fujikado, T., Matsumura, K., Terashima, T., Toda, T.: "Fukutin is required for maintenance of muscle integrity, cortical histiogenesis, and normal eye development"Hum. Molec. Genet.. 12. 1449-1459 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Toda, T., Kobayashi, K.,.Takeda, S., Sasaki, J., Kurahashi, H., Kano, H., Tachikawa, M., Wang, F., Nagai, Y., Taniguchi, K., Taniguchi, M., Sunada, Y., Terashima, T., Endo, T., Matsumura, K.: "Fukuyama-type congenital muscular dystrophy (FCMD) and α-dystroglycanopathy"Congenital Anomalies. 43. 97-104 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Saito, F., Ohi, H.F., Shimizu, T., Matsumura, K.: "The role of dystroglycan in the pathogenesis of neuromuscular disorders and infectious diseases"Recent Res. Devel. Biochem.. 4. 561-573 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Matsumura, K., Arai, K., Zhong, D., Saito, F., Ohi, H.F., Maekawa, R., Yamada, H., Shimizu, T.: "Disruption of dystroglycan axis by β-dystroglycan processing in cardiomyopathic hamster muscle"Neuromusc. Disord.. 13. 796-803 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Saito, F., Tomimitsu, H., Arai, K., Kanda, T., Mizusawa, H., Shimizu, T., Matsumura, K.: "A Japanese patient with distal myopathy with rimmed vacuoles : Missense muta-tions in the epimerase domain of the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene accompanied by hyposialylation of skeletal muscle glycoproteins"Neuromusc. Disord. 14. 158-161 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Matsumura, K., Arai, K., Zhong, D., Saito, F., Fukuta-Ohi, H., Maekawa, R., Yamada, H, Shimizu, T.: "Matrix metalloproteinase activity that disrupts the dystroglycan complex: its role in the molecular pathogenesis of muscular dystrophies"Basic and Applied Myology. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Toda, T., Kobayashi, K., Takeda, S., Sasaki, J., Kurahashi, H., Kano, H., Tachikawa, M., Wang, F., Nagai, Y., Taniguchi, K., Taniguchi, M., Sunada, Y., Terashima, T., Endo, T., Matsumura, K.: "Fukuyama-type congenital muscular dystrophy and abnormal glycosylation of a-dystroglycan"Basic and Applied Myology. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Masaki, T., Matsumura, K., Saito, F., Kamakura, K., Yorifuji, H., Shimizu, T.: "Association of dystroglycan and larninin-2 co-expression with myelinogensis"Medical Electron Microscopy. (in press).

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2005-04-19  

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