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1995 Fiscal Year Final Research Report Summary

DEVELOPMENT OF A THERAPY FOR DUCHENNE MUSCULAR DYSTROPHY BY DRPUPREGULATION

Research Project

Project/Area Number 05557037
Research Category

Grant-in-Aid for Developmental Scientific Research (B)

Allocation TypeSingle-year Grants
Research Field Neurology
Research InstitutionTEIKYO UNIVERSITY

Principal Investigator

SHINIZU Teruo  TEIKYO UNIVERSITY,DEPARTMENT OF NEUROLOGY,PROFESSOR, 医学部, 教授 (00107666)

Co-Investigator(Kenkyū-buntansha) YAMADA Hiroki  TEIKYO UNIVERSITY,DEPARTMENT OF NEUROLOGY,RESEARCH FELLOW, 医学部, 助手 (90260926)
USUKI Fusako  TEIKYO UNIVERSITY,DEPARTMENT OF NEUROLOGY,LECTURER, 医学部, 講師 (50185013)
MATSUMURA Kiichiro  TEIKYO UNIVERSITY,DEPARTMENT OF NEUROLOGY,ASSOCIATE PROFESSOR, 医学部, 助教授 (50260922)
Project Period (FY) 1993 – 1995
KeywordsDYSTROPHIN EXPRESSION FACTOR / DRP / UTROPHIN / Dp116 / SCHWANN CELL / DYSTROGLYCAN COMPLEX / LAMININ / SIALIC ACID
Research Abstract

The project started at 1993 to aim to develop a new therapy for Duchenne muscular dystrophy by study of regulatory mechanism of a dystrophin homologue, DRP or utrophin. The first goals were 1.analysis of total DRP gene structure, 2.development of a specific antiDRP antibody, and 3.determination of regulatory factors for DRP gene expression. At the beginning of the project, goal 1 was achieved by other investigators and the second goal 2 was done. The antiDRP spcific antibody and DRP message disclosed a wide expression of DRP protein or message in varied tissues including endothelial cells and nervous tissues. In addition, it was supprised that DRP was not only localized at plasm membrane but also in the cytoplasma. The data suggest that DRP may play a unclarified but important rloe (s) in a wide variety of cells. Regulatory factors for DRP gene expression could not be identified, although dibutyryl cAMP was found to be a specific upregulator for dystrophin. Physiological function of DRP is now essential for development of a therapy for DMD,because upregulation of DRP can play a unexpected function in nonmuscle cells.
For study of DRP in nonmuscle cells, we choosed Schwann cells because of the amount of DRP expression. In Schwann cells, DRP and dystrophin isoform, Dp116, was identified at both plasma membrane and cytoplasma by immunostainings. So-called dystrophin-associated (glyco) proteins (DAGs) were quite different in Schwann cell from muscle. 1.Dystroglycan complex were alpha dystroglycan, 120kD in stead of 156kD in muscle, and beta dystroglycan, 43kD,2.sarcoglycan complex was not present, 3.syntrophin complex was not identified. Dystroglycan complex was a dual receptor for nervous laminin and agrin dependent on Ca ions. Sialic acid was essential for binding between laminin/agrin and alpha dystroglycan. We are now going to analyze myelinogenesis in mutation of DRP/Dp116, dystroglycan complex and/or laminin/agrin.

  • Research Products

    (14 results)

All Other

All Publications (14 results)

  • [Publications] Yamada H et al.: "Characterization of dystroglycan-laminin interaction in peripheral nerve" Journal of Neurochemistry. (in press).

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yamada H et al.: "Secretion of laminin α2 chain in cerebrospinal fluid" FEBS Letters. 376. 37-40 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yamada H et al.: "Laminin abnormalities in severe childhood autosomal recessive muscular dystrophy" Laboratory Investigation. 72. 715-722 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kawai H et al.: "Adhalin gene mutations in patients with autosomal recessive childhood onset muscular dystrophy with adhalin deficiency" Journal of Clinical Investigation. 96. 1202-1207 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Higuchi I et al.: "Abnormal expression of heparan sulfate proteoglycan on basal lamina of muscle fibers in two Japanese patients with adhalin deficiency" Neuromuscular Disorders. 5. 467-474 (1995)

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      「研究成果報告書概要(和文)」より
  • [Publications] Toda T et al.: "Three-dimensional MR imaging of brain surface anomalies in Fukuyama-type congenital muscular dystrophy" Muscle Nerve. 18. 508-517 (1995)

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      「研究成果報告書概要(和文)」より
  • [Publications] Yamada H et al: "Dystroglycan is a dual receptor for agrin and laminin in Schwann cell membrane" J Biol Chem. (accepted).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Usuki F et al: "Up-regulation of dystrophin mRNA by exposure to dibutyryl cAMP in the C2C12 muscle cell line" Biochem Biophys Res Comm. 210. 654-659 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yamada H et al: "Secretion of laminina2 chain in cerebral fluid" FEBS Lett. 376. 37-40 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kawai H et al: "Adhalin gene mutations in patients with autosomal recessive childhood onset muscular dystrophy with adhalin deficiency" J Clin Invest. 96. 1202-1207 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ymada H et al: "Laminin abnormality in severe childhood autosomal recessive muscular dystrophy" Lab Invest. 72. 715-722 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yamada H et al: "Dystroglycan is a binding protein of laminin and merosin in peripheral nerve" FEBS Lett. 352. 49-53 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Higuchi I et al: "Abnormal expression of laminin suggests disturbance of sarcolemma-extracellular matrix interaction in Japanese patients with autosomal recessive muscular dystrophy decicient in adhalin" J Clin invest. 94. 601-606 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Matsumura K et al: "Differential expression of dystrophin, utrophin and dystrophin-associated proteins in peripheral nerve" FEBS Lett. 334. (1993)

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

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Published: 1999-03-09  

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