• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Analysis of mechanisms of demyelination in progressive multifocal leukoencephalopathy

Research Project

Project/Area Number 10357002
Research Category

Grant-in-Aid for Scientific Research (A).

Allocation TypeSingle-year Grants
Section展開研究
Research Field Human pathology
Research InstitutionHOKKAIDO UNIVERSITY

Principal Investigator

NAGASHIMA Kazuo  Hokkaido Univ., Grad.School.of Med., Pro., 大学院・医学研究科, 教授 (50010377)

Co-Investigator(Kenkyū-buntansha) TANAKA Shinya  Hokkaido Univ., Grad.School.of Med., Lecturer, 大学院・医学研究科, 講師 (70261287)
SAWA Hirofumi  Hokkaido Univ., Grad.School.of Med., Asso.Pro, 大学院・医学研究科, 助教授 (30292006)
Project Period (FY) 1998 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥23,100,000 (Direct Cost: ¥23,100,000)
Fiscal Year 2000: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1999: ¥5,100,000 (Direct Cost: ¥5,100,000)
Fiscal Year 1998: ¥15,000,000 (Direct Cost: ¥15,000,000)
KeywordsJC virus (JCV) / cellular receptor / sialic acids / regulatory region / transcriptional factor / agnoprotein / HTLV- I TAX / 転写調節領域 / yeast two hybrid / veast two hybrid system
Research Abstract

JC virus (JCV) causes in humans a demyelinating disease, progressive multifocal leukoencephalopathy (PML), but mechanisms of demyelination by JCV remain unknown.
To investigate early events of JCV infection including attachment, penetration, and transport to the nuclei where viral replication occurs, we have analyzed the susceptibility of 15 different cell lines to infection using a semi-quantitative PCR assay, ISH, laser scanning confocal microscopy and a viral replication assay. JCV entry was observed in all cell lines within 10 min after inoculation. Inhibition of viral entry both by an anti-JCV VP1 antibody and sialidase treatment to remove sialic acid residues argues in favor that JCV VP1 functions as ligand and that JCV receptor is the cellular surface molecules containing sialic acids. In addition, chlorpromazine, a clathrin-dependent pathway inhibitor, significantly suppressed entry of JCV into nuclei, suggesting that JCV utilizes a clathrin pathway during the entry to cells. Fr … More om these observations it has been proved that JCV receptor is broadly expressed in the cells originated from various tissues and species.
Because the recent clinicopathological analyses have disclosed that human T-lymphotropic virus type I (HTLV-I) could be an underlying disease of PML, we have examined whether the HTLV-I encoded regulatory protein Tax activates JCV transcription. Using a dual luciferase assay and an electrophoretic mobility shift assay (EMSA), we found the expression of HTLV-I Tax activated the transcriptional potential of both early and late promoters of JCV in human neural cells in a NF-κB-dependent manner. In addition, we demonstrated the presence of Tax-bound protein(s) which were specifically present in non-neural cells.
We also found that agnoprotein, one of the JCV late proteins, enhanced the JCV promoter itself. These results make it possible to establish an effective therapy against PML based on the mechanism of viral infection and multiplication in the neural cells. Less

Report

(4 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • 1998 Annual Research Report

Research Products

(42 results)

All Other

All Publications (42 results)

  • [Publications] Mochizuki N., et al.: "Activation of the ERK/MAPK pathway by an isoform of rap 1 GAP associated with G αi."Nature. 400. 891-894 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Takahashi RH., et al.: "Analysis of human lymphotropic T-cell virus Type II-like particle production by recombinant Baculovirus-infected insect cells."Virology. 256. 371-380 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Takahashi H., et al: "Characterization of antibodies raised against bovine-PrP-peptides."J Neurovirol. 5. 300-307 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nagashima T., et al.: "Adult Leigh syndrome with mitochondrial DNA mutation at 8993."Acta Neuropathol. 97. 416-422 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Okada Y., et al.: "Transcriptional activation of JC virus by human T-lymphotropic virus Type 1 Tax protein in human neuronal cell lines."J Biol Chem. 275. 17016-17023 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Shintaku M., et al.: "Infection with JC virus and possible dysplastic ganglion-like transformation of the cerebral cortical neurons in a case of progressive multifocal leukoencephalopathy."J Neuropathol Exp Neurol. 59. 921-929 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Shishido-Hara Y., et al.: "Analysis of capsid formation of human polyomavirus JC (Tokyo-1 stain) by a eukaryotic expression system : Splicing of late RNAs, translation and nuclear transport of major capsid protein VP1, and capsid assembly."J Virol 74. 74. 1840-1853 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nagashima T., et al.: "Oculopharyngeal muscular dystrophy in a Japanese family with a short GCG expansion (GCG)_<11> in PABP2 gene."Neuromuscul Disord. 10. 173-177 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ohba Y., et al: "Rap2 as a slowly responding molecular switch in the Rap1 signaling cascade."Mol Cell Biol. 20. 6074-6083 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yamashita S., et al.: "CalDAG-GEFIII activation of Ras, R-Ras, and Rap1."J Biol Chem. 275. 25488-25493 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ohba Y., et al.: "Regulatory proteins of R-Ras, TC21/R-Ras2, and M-Ras/R-Ras3."J Biol Chem. 275. 20020-20026 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Takahashi H., et al.: "Monoclonal antibodies against topoisomerase I suppressed DNA relaxation and HIV-1 cDNA synthesis."Hybridoma. 19. 331-334 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Mochizuki N, Ohba Y, Kiyokawa E, Kurata T, Murakami T, Ozaki T,Kitabatake A, Nagashima K, Matusda M.: "Activation of the ERK/MAPK pathway by an isoform of rap 1 GAP associated with Gαi."Nature. 400. 891-894 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Takahashi RH, Nagashima K, Kurata T, Takahashi H.: "Analysis of human lymphotropic T-cell virus Type II-like particle production by recombinant Baculovirus-infected insect cells."Virology. 256. 371-380 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Takahashi H, Takahashi RH, Hasegawa H, Horiuchi M, Shinagawa M, Yokoyama T, Kimura K, Haritani M, Kurata T, Nagashima K.: "Characterization of antibodies raised against bovine-PrP-peptides."J Neurovirol. 5. 300-307 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nagashima T, Mori M, Katayama K, Nunomura M, Nishihara H, Hiraga H, Tanaka S, Goto Y, Nagashima K.: "Adult Leigh syndrome with mitochondrial DNA mutation at 8993."Acta Neuropathol. 97. 416-422 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Okada Y, Sawa H, Tanaka S, Takada A, Suzuki S, Hasegawa H, Umemura T, Fujisawa J, Tanaka Y, Hall WW, Nagashima K.: "Transcriptional activation of JC virus by human T-lymphotropic virus Type 1 Tax protein in human neuronal cell lines."J Biol Chem. 275. 17016-17023 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Shintaku M, Matsumoto R, Sawa H, Nagashima K.: "Infection with JC virus and possible dysplastic ganglion-like transformation of the cerebral cortical neurons in a case of progressive multifocal leukoencephalopathy."J Neuropathol Exp Neurol. 59. 921-929 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Shishido-Hara Y, Hara Y, Larson T, Yasui K, Nagashima K, Strner GL.: "Analysis of capsid formation of human polyomavirus JC (Tokyo-1 stain) by a eukaryotic expression system : Splicing of late RNAs, translation and nuclear transport of major capsid protein VP1, and capsid assembly."J Virol. 74. 1840-1853 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nagashima T, Kato H, Kase M, Maguchi S, Mizutani Y, Matsuda K, Chuma T, Mano Y, Goto Y, Minami N, Nonaka I, Nagashima K.: "Oculopharyngeal muscular dystrophy in a Japanese family with a short GCG expansion (GCG)_<11> in PABP2 gene."Neuromuscul Disord. 10. 173-177 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ohba Y, Mochizuki N, Matsuo K, Yamashita S, Nakaya M, Hashimoto Y, Hamaguchi M, Kurata T, Nagashima K, Matsuda M.: "Rap2 as a slowly responding molecular switch in the Rap1 signaling cascade."Mol Cell Biol. 20. 6074-6083 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yamashita S, Mochizuki N, Ohba Y, Tobiume M, Okada Y, Sawa H, Nagashima K, Matsuda M: "CalDAG-GEFIII activation of Ras, R-Ras, and Rap1."J Biol Chem. 275. 25488-25493 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ohba Y, Mochizuki N, Yamashita S, Chan AM, Schrader JW, Hattori S, Nagashima K, Matsuda M.: "Regulatory proteins of R-Ras, TC21/R-Ras2, and M-Ras/R-Ras3."J Biol Chem. 275. 20020-20026 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Takahashi H, Iwata T, Kitagawa Y, Shoya Y, Takahashi RH, Nagashima K, Kurata T.: "Monoclonal antibodies against topoisomerase I suppressed DNA relaxation and HIV-1 cDNA synthesis."Hybridoma. 19. 331-334 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Okada Y, et al.: "Transcriptional activation of JC virus by human T-lymphotrpic virus Type 1 tax protein in human neuronal cell kines."J Biol Chem. 275. 17016-17023 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ohba Y, et al..: "Regulatory proteins of R-Ras, TC21/R-Ras2, and M-Ras/R-Ras3."J Biol Chem. 275. 20020-20026 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Shintaku M, et al..: "Infection with JC virus and possible dysplastic Ganglion-like transformation of the cerebral cortical neurons in a case of Progressive multifocal leukoencephalopathy."J Neuropathol Exp Neurol. 59. 921-929 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ohba Y, et al.: "Rap2 as a slowly responding molecular switch in the Rap1 signaling cascade."Mol Cell Biol. 20. 6074-6083 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yamamoto Y, et al.: "CalDAG-GEFIII activation of Ras, R-Ras, and Rap1."J Biol Chem. 275. 25488-25493 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Takahashi H, et al.: "Monoclonal antibodies against Topoisomerase I suppressed DNA relaxation and HIV-1 cDNA synthesis."Hybridoma. 19. 331-334 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Shishido-Hara Y, et al.: "Analysis of capsid formation of human polyomavirus JC (Tokyo-1 strain) by a eukaryotic expression system : splicing of late RNAs, translation and nuclear transport of major capsid protein VP1, and capsid assembly."J Virol. 174. 1840-1853 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Takahashi, RH., et al: "Analysis of human lymphotropic T-cell virus type II-like particle production by recombinant baculovirus-infected insect cells"Virology. 256. 371-180 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Nagashima, T., et al.: "Wernicke encephalopathy-like symptoms as an early manifestation of Creutzfeldt-Jakob disease in a chronic alcoholic"J Neurol Sci. 163(2). 192-198 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Suzuki, G., et al.: "Pertussis toxin-sensitive signal controls the trafficking of thymocytes across the corticomedullary junction in the thymus"J Immunol. 162. 5981-5985 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Takahashi, H., et al.: "Characterization of antibodies raised against bovine-PrP-peptides"J Neurovirol. 5. 300-307 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Takahashi, H., et al.: "Increased levels of and isoforms of 14-3-3 proteins in cerebrospinal fluid in patients with Creutzfeldt-Jakob disease"Clin Diagn Lab Immunol. 6. 983-985 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Suzuki, T., et al.: "A method for detection of a cytokine and its mRNA in the central nervous system of the developing rat"Brain Res Brain Res Protoc. 4(3). 271-279 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Shishido-Hara, Y., et al.: "Analysis of capsid formation of human polyomavirus JC (Tokyo-1 strain) by a eukaryotic expression system : splicing of late RNAs, translation and nuclear transport of major capsid protein VP1, and capsid assembly"J Virol. 174. 1840-1853 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kitamura T.,et al.: "Peopling of Japan as revealed by genotyping of urinary JC virus DNA" Anthropological Science. 106(4). 311-325 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Wakutani Y.,et al.: "A case of brain-biopsy proven progressive multifocal leukoencephalopathy : Pathological findings and analysis of JC virus regulatory region" Neuropathology. 18(3). 347-351 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Itoh S.,et al.: "Involvement of cell membrane factors in JC virus infection" Neuropathology. 18(1). 67-72 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Sugimoto C.,et al.: "Amplification of JC virus regulatory DNA sequences from cerebrospinal fluid : diagnostic value for progressive multifocal leukoencephalopathy" Archives of Virology. 143(2). 249-262 (1998)

    • Related Report
      1998 Annual Research Report

URL: 

Published: 1998-03-31   Modified: 2016-04-21  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi