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THE RESEARCH OF THE THERAPY FOR GAUCHER DISEASE WITH CENTRAL NERVOUS INVOLVEMENT BY THE LOW MOLECULAR COMPOUNDS.

Research Project

Project/Area Number 14570746
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Pediatrics
Research InstitutionTottori University

Principal Investigator

NANBA Eiji (2004)  TOTTORI UNIVERSITY, RESEARCH CENTER FOR BIOSCIENCE AND TECHNOLOGY, PROFESSOR, 生命機能研究支援センター, 教授 (40237631)

岡 明 (2002-2003)  鳥取大学, 医学部, 助教授 (00251273)

Co-Investigator(Kenkyū-buntansha) INOUE Takehiko  TOTTORI UNIVERSITY, INSTITUTE OF NEUROLOGICAL SCIENCES, ASSISTANT PROFESSOR, 医学部附属病院, 助手 (80346361)
難波 栄二  鳥取大学, 生命機能研究支援センター, 教授 (40237631)
赤星 進二郎  鳥取大学, 医学部, 講師 (90231810)
Project Period (FY) 2002 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2004: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2003: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2002: ¥1,500,000 (Direct Cost: ¥1,500,000)
KeywordsGaucher disease / Therapy / Low molecular compound / Carba-sugar / Lysosome / 分子シャペロン / β-グルコセレブロシダーゼ / 分子シャペロン療法 / ライソゾーム病 / 先天代謝異常
Research Abstract

Gaucher disease(GD) is the most common form of sphingolipidosis and is caused by a defect of beta-glucosidase (beta-Glu). A carbohydrate mimic N-octyl-beta-valienamine(NOV) is an inhibitor of beta-Glu. When applied to cultured GD fibroblasts with F213I beta-Glu mutation, NOV increased the protein level of the mutant enzyme and up-regulated cellular enzyme activity. The maximum effect of NOV was observed in F213I homozygous cells in which NOV treatment at 30 microM for 4 days caused a approximately 6-fold increase in the enzyme activity, up to approximately 80% of the activity in control cells. NOV was not effective in cells with other beta-Glu mutations, N370S,L444P,84CG and RecNciI. Immunofluorescence and cell fractionation showed localization of the F213I mutant enzyme in the lysosomes of NOV-treated cells. Consistent with this, NOV restored clearance of 14C-labeled glucosylceramide in F213I homozygous cells. F213I mutant beta-Glu rapidly lost its activity at neutral pH in vitro and this pH-dependent loss of activity was attenuated by NOV. These results suggest that NOV works as a chemical chaperone to accelerate transport and maturation of F213I mutant beta-Glu and may suggest a therapeutic value of this compound for GD.

Report

(4 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • Research Products

    (41 results)

All 2005 2004 2003 2002 Other

All Journal Article (30 results) Publications (11 results)

  • [Journal Article] Proteasomal degradation of Kir6.2 channel protein and its inhibition by a Na(+) channel blocker aprindine.2005

    • Author(s)
      Tanaka H et al.
    • Journal Title

      Biochem Biophys Res Commun. 331

      Pages: 1001-1006

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] A non-NF2 case of schwannomas of vestibular and trigeminal nerves with different mutations of NF2 gene.2005

    • Author(s)
      Kambe A et al.
    • Journal Title

      Surg Neurol 63

      Pages: 62-65

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] A non-NF2 case of schwannomas of vestibular and trigeminal nerves with different mutations of NF2 gene.2005

    • Author(s)
      Kambe A, Kamitani H, Watanabe T, Oka A, Inagaki H, Ishii T, Ueki K.
    • Journal Title

      Surg Neurol 63

      Pages: 62-65

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Proteasomal degradation of Kir6.2 channel protein and its inhibition by a Na(+) channel blocker aprindine.2005

    • Author(s)
      Tanaka H, Miake J, Notsu T, Sonyama K, Sasaki N, Iitsuka K, Kato M, Taniguchi S, Igawa O, Yoshida A, Shigemasa C, Hoshikawa Y, Kurata Y, Kuniyasu A, Nakayama H, Inagaki N, Nanba E, Shiota G, Morisaki T, Ninomiya H, Kitakaze M, Hisatome I.
    • Journal Title

      Biochem Biophys Res Commun. 331(4)

      Pages: 1001-1006

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] N-octyl-beta-valienamine up-regulates activity of F213I mutant beta-glucosidase in cultured cells : a potential chemical chaperone therapy2004

    • Author(s)
      Lin H et al.
    • Journal Title

      Biochim Biophys Acta 1689

      Pages: 219-228

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Increased NPC1 mRNA in skin fibroblasts from Niemann-Pick disease type C patients.2004

    • Author(s)
      Yamamoto T et al.
    • Journal Title

      Brain Dev 26・4

      Pages: 245-250

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Girl with monosomy 1p36 and Angelman syndrome due to unbalanced der(1) transmission of a maternal translocation t(1;15)(p36.3;q13.1)2004

    • Author(s)
      Torisu Y et al.
    • Journal Title

      Am J Med Genet 131A

      Pages: 94-98

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Altered Expression of ARPP Protein in Skeletal Muscles of Patients with Muscular Dystrophy, Congenital Myopathy and Spinal Muscular Atrophy.2004

    • Author(s)
      Nakada C et al.
    • Journal Title

      Pathobiology 71

      Pages: 43-51

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation.2004

    • Author(s)
      Kato M et al.
    • Journal Title

      Hum Mutat 23

      Pages: 147-159

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation.2004

    • Author(s)
      Kato M, Das S, Petras K, Kitamura K, Morohashi K, Abuelo DN, Barr M, Bonneau D, Brady A, Carpenter NJ, Frisone F, Fukuda T, Guerrini R, Iida E, Itoh M, Lewanda AF, Nanba Y, Oka A, Proud VK, Russel KL, Saugier-Veber P, Schelley SL, Selicorni A, Shaner R, Silengo M, Stewart F, Sugiyama N, Toyama J, Toutain A, Vargas AL, Yanazawa M, Zackai EH, Dobyns WB.
    • Journal Title

      Hum Mutat 23

      Pages: 147-159

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Altered Expression of ARPP Protein in Skeletal Muscles of Patients with Muscular Dystrophy, Congenital Myopathy and Spinal Muscular Atrophy.2004

    • Author(s)
      Nakada C, Tsukamoto Y, Oka A, Nonaka I, Sato K, Mori S, Ito H, Moriyama M.
    • Journal Title

      Pathobiology 71

      Pages: 43-51

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Girl with monosomy 1p36 and Angelman syndrome due to unbalanced der(1) transmission of a maternal translocation t(1;15)(p36.3;q13.1).2004

    • Author(s)
      Torisu Y, Yamamoto T, Fujiwaki T, Kadota M, Oshimura M, Kurosawa K, Akaboshi S, Oka A.
    • Journal Title

      Am J Med Genet 131A(1)

      Pages: 94-98

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] N-Octyl-β-valienamine up-regulates activity of F213I mutant β-glucosidase in cultured cells : a potential chemical chaperone therapy for Gaucher disease.2004

    • Author(s)
      Lin H, Sugimoto Y, Ohsaki Y, Ninomiya H, Oka A, Taniguchi M, Ida H, Eto Y, Ogawa S, Matsuzaki Y, Sawa M, Inoue T, Higaki K, Nanba E, Ohno K, Suzuki Y.
    • Journal Title

      Biochimica et Biophysica Acta 1689

      Pages: 219-228

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Increased NPC1 mRNA in skin fibroblasts from Niemann-Pick disease type C patients.2004

    • Author(s)
      Yamamoto T, Feng JH, Higaki K, Taniguchi M, Nanba E, Ninomiya H, Ohno K.
    • Journal Title

      Brain Dev. 26(4)

      Pages: 245-250

    • NAID

      10020552645

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] N-octyl-beta-valienamine up-regulates activity of F213I mutant beta-glucosidase in cultured cells : a potential chemical chaperone therapy for Gaucher disease.2004

    • Author(s)
      Lin H et al.
    • Journal Title

      Biochim Biophys Acta 1689

      Pages: 219-228

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Increased NPC1 mRNA in skin fibroblasts from Niemann-Pick disease type C patients.2004

    • Author(s)
      Yamamoto T et al.
    • Journal Title

      Brain Dev.2004 26・4

      Pages: 245-250

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Chemical chaperone therapy for brain pathology in GM1-gangliosidosis.2003

    • Author(s)
      Matsuda J et al.
    • Journal Title

      Proc Natl Acad Sci U S A 100

      Pages: 15912-15917

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Vertebral artery dissection in an infant : ultrastructural aberrations of connective tissue components.2003

    • Author(s)
      Ogura K et al.
    • Journal Title

      Neuropediatrics 34

      Pages: 307-310

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] New GAA mutations in Japanese patients with GSDII (Pompe disease).2003

    • Author(s)
      Pipo JR et al.
    • Journal Title

      Pediatr Neurol 29

      Pages: 284-287

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Cardiac ankyrin repeat protein is preferentially induced in atrophic myofibers of congenital myopathy and spinal muscular atrophy.2003

    • Author(s)
      Nakada C et al.
    • Journal Title

      Pathol Int 53

      Pages: 653-658

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Cardiac-restricted ankyrin-repeated protein is differentially induced in Duchenne and congenital muscular dystrophy.2003

    • Author(s)
      Nakada C et al.
    • Journal Title

      Lab Invest 83

      Pages: 711-719

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Myelin transcription factor 1(Myt1) immunoreactivity in infants with periventricular leukomalacia.2003

    • Author(s)
      Hirayama A et al.
    • Journal Title

      Dev Brain Res 140

      Pages: 85-92

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Myelin transcription factor 1 (Myt1) immunoreactivity in infants with periventricular leukomalacia.2003

    • Author(s)
      Hirayama A, Oka A, Ito Masayuki, Tanaka F, Ohkoshi Y, Takashima S.
    • Journal Title

      Dev Brain Res 140

      Pages: 85-92

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Cardiac-restrcted ankyrin-repeated protein is differentially induced in Duchenne and congenital muscular dystrophy.2003

    • Author(s)
      Nakada C, Tsukamoto Y, Oka A, Nonaka I, Takeda I, Sato K, Mori S, Ito H, Moriyama M.
    • Journal Title

      Lab Invest 83

      Pages: 711-719

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Cardiac ankyrin repeat protein is preferentially induced in atrophic myofibers of congenital myopathy and spinal muscular atrophy.2003

    • Author(s)
      Nakada C, Oka A, Nonaka I, Sato K, Mori S, Ito H, Moriyama M.
    • Journal Title

      Pathol Int 53

      Pages: 653-658

    • NAID

      50000346440

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] New GAA mutations in Japanese patients with GSDII (Pompe disease).2003

    • Author(s)
      Pipo JR, Feng JH, Yamamoto T, Ohsaki Y, Nanba E, Tsujino S, Sakuragawa N, Martiniuk F, Ninomiya H, Oka A, Ohno K.
    • Journal Title

      Pediatr Neurol 29

      Pages: 284-287

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Vertebral artery dissection in an infant : ultrastructural aberrations of connective tissue components.2003

    • Author(s)
      Ogura K, Oka A, Ohno K.
    • Journal Title

      Neuropediatrics 34

      Pages: 307-310

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Chemical chaperone therapy for brain pathology in G(M1)-gangliosidosis.2003

    • Author(s)
      Matsuda J, Suzuki O, Oshima A, Yamamoto Y, Noguchi A, Takimoto K, Itoh M, Matsuzaki Y, Yasuda Y, Ogawa S, Sakata Y, Nanba E, Higaki K, Ogawa Y, Tominaga L, Ohno K, Iwasaki H, Watanabe H, Brady RO, Suzuki Y.
    • Journal Title

      Proc Natl Acad Sci USA. 100(26)

      Pages: 15912-15917

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Unilateral occlusion of the middle cerebral artery after varicella-zoster virus infection.2002

    • Author(s)
      Ueno M et al.
    • Journal Title

      Brain Dev 24

      Pages: 106-108

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Unilateral occlusion of the middle cerebral artery after varicella-zoster virus infection.2002

    • Author(s)
      Ueno M, Oka A, Koeda T, Okamoto R, Takeshita K.
    • Journal Title

      Brain Dev 24

      Pages: 106-108

    • NAID

      10010103555

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Pipo JR, Feng JHa N, Martiniuk F, Ninomiya H, Oka A, Oh, Yamamoto T, Ohsaki Y, Nanba E, Tsujino S, Sakuragawno K.: "New GAA mutations in Japanese patients with GSDII (Pompe disease)."Pediatr Neurol. 29巻. 284-287 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nakada C, Tsukamoto Y, Oka A, Nonaka I, Takeda I, Sato K, Mori S, Ito H, Moriyama M.: "Cardiac-restrcted ankyrin-repeated protein is differentially induced in Duchenne and congenital muscular dystrophy."Lab Invest. 83巻. 711-719 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nakada C, Oka A, Nonaka I, Sato K, Mori S, Ito H, Moriyama M.: "Cardiac ankyrin repeat protein is preferentially induced in atrophic my ofibers of congenital myopathy and spinal muscular atrophy."Pathol Int. 53巻. 653-658 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ogura K, Oka A, Ohno K.: "Vertebral artery dissection in an infant : ultrastructural aberrations of connective tissue components."Neuropediatrics. 34巻. 307-310 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nakada C, Tsukamoto Y, Oka A, Nonaka I, Sato K, Mori S, Ito H, Moriyama M.: "Altered Expression of ARPP Protein in Skeletal Muscles of Patients with Muscular Dystrophy, Congenital Myopathy and Spinal Muscular Atrophy."Pathobiology. 71巻. 43-51 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hirayama A, Oka A, Ito M, Tanaka F, Ohkoshi Y, Takashima S: "Myelin transcription factor 1 (Myt1) immunoreactivity in infants with periventricular leukomalacia"Developmental Brain Research. 140巻. 85-92 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nakada C, Tsukamoto Y, Oka A, Nonaka I, Sato K, Mori S, Ito H, Moriyama M: "Altered expression of ARPP protein in skeletal muscles of patient with museular dystrophy, dongenital myopathy and spinal muscular atrophy"Pathobiology. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] Nakada C, Oka A, Nonaka I, Sato K, Mori S, Ito M, Moriyama M: "Cardial onkyrin reperted protein is induced in atrophic nyofibers of conquenital myoparhy and spinal muscular atrophy"Laboratory Investigation. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] Shiroma, N.Kanazawa, Z.Kato, N.Shimozawa, A.Imamura, M.Ito, K.Ohtani, A.Oka, K.Wakabayashi, M.Iai, K.Sugai, M.Sasaki, M.Kaga, T.Ohta, S.Tsujino: "Molecular genetic study in Japanese patients with Alexander disease: a novel mutation, R79L"Brain and Development. 25. 116-121 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Takaura N, Yagi T, Maeda M, Nanba E, Matsuda J, Oshima A, Suzuki Y, Yamano T, Yanaka T: "Attenuation of ganglioside GM1 accumulation in the brain of GM1 gangliosidosis mice by neonatal intravenous gene"Gene Therapy. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] Saito Y, Suzuki K, Nanba E, Yamamoto T, Ohno K, Murayama S: "Niemann-Pick type C disease: accelerated neurofibrillary tangle formation and amyloid beta deposition associated with apoliporotein Ee4 homozygosity"Annol Neurology. 52. 351-355 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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