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STRATEGIC RESEARCH FOR POSSIBLE SUPPRESSION OF NEURONAL DEATH BY CASPASE INHIBITORS

Research Project

Project/Area Number 12357004
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Neurology
Research InstitutionThe University of Tokyo

Principal Investigator

KANAZAWA Ichiro  DEPARTMENT OF NEUROLOGY, PROFESSOR, 医学部附属病院, 教授 (30110498)

Co-Investigator(Kenkyū-buntansha) MURATA Miho  DEPARTMENT OF NEUROLOGY, RESEARCH ASSOCIATE, 医学部附属病院, 助手 (30282643)
GOTO Jun  DEPARTMENT OF NEUROLOGY, RESEARCH ASSOCIATE, 医学部附属病院, 助手 (10211252)
KWAK Shin  DEPARTMENT OF NEUROLOGY, ASSOCIATE PROFESSOR, 医学部附属病院, 助教授 (40160981)
MASAYASU Hiroyuki  DAIICHI DRUG COMPANY, GROUP CHIEF (Researcher), 医薬開発企画部, グループ長(研究職)
Project Period (FY) 2000 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥43,520,000 (Direct Cost: ¥39,200,000、Indirect Cost: ¥4,320,000)
Fiscal Year 2001: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000)
Fiscal Year 2000: ¥24,800,000 (Direct Cost: ¥24,800,000)
KeywordsCASPASES / CAG REPEAT DISEASES / NEURONAL CELL DEATH / CASPASE INHIBITORS / パーキンソン病 / 蛋白質分解酵素 / カテプシン / 酵素活性阻害
Research Abstract

Caspases are partly accepted as responsible molecules for neuronal death particularly due to apoptosis. At first, we postulated to suppress neuronal death by inhibition of caspases. However, it was practically difficult to do so mainly because caspase inhibitors are not specific for each substrate. When we investigated the relationship between nuclear morphology and activities of caspases (caspase 1,2,3,6,9) in cultured cells, SHSY5Y, we found a clear discrepancy. In fact, caspase activities were normal even when nuclei were apoptotically segmented. These findings, however, are largely predictable and not novel. Then, we made a plan to suppress the disease process by a different method. Since GAG repeat expansion diseases are caused by the expression of the abnormal gene products, we planned to supress the disease by using a method based on RNAi. This budget was used for the latter project effectively.

Report

(3 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • Research Products

    (26 results)

All Other

All Publications (26 results)

  • [Publications] Yoshizawa T, Yamagishi Y, Koseki N, Goto J, Yoshida H, Shibasaki F, Shoji S, Kanazawa I: "Cell cycle arrest enhances the in vitro cellular toxicity of the truncated Machado-Joseph disease gene product with an expanded polyglutamine stretch"Human Molecular Genetics. 9(1). 69-78 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Wang GH, Sawai N, Kotliarova S, Kanazawa I, Nukina N: "Ataxin-3, the MJD1 gene product, interacts with the two human homologs of yeast DNA repair protein RAD23, HHR23A and HHR23B"Human Molecular Genetics. 9(12). 1795-1803 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hazeki N, Tukamoto I, Goto J, Kanazawa I: "Formic acid dissolves aggregates of an N-terminal Huntingtin fragment containing an expanded polyglutamine tract : appolying to quantification of protein components of the aggregates"Biochemical Biophysical Research Communication. 277. 386-393 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kanazawa I: "How do neurons die in neurodegenerative diseases?"Trends in Molecular Medicine. 7(8). 339-344 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Nakamura K, Jeong SY, Uchihara T, Anno M, Nagashima K, Nagashima T, Ikeda S, Tsuji S, Kanazawa I: "SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein"Human Molecular Genetics. 10(14). 1441-1448 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hashida H, Goto J, Suzuki T, Jeong SY, Masuda N, Ooie T, Tachiiri Y, Tsuchiya H, Kanazawa I: "Single cell analysis of CAG repeat in brains of dentatorubral-pallidoluysian atrophy (DRPLA)"Journal of Neurological Sciences. 190. 87-93 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kanazawa I: "Gulutamine Repeats and Neurodegenerative Diseases : Molecular Aspects (Molecular pathology of dentatorubral-pallidoluysian atrophy)"Harper P & Perutz M, Oxford University Press Inc, New York. 249-260 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yoshizawa T, Yamagishi Y, koseki N, Goto J, Yoshida H, Shibasaki F, Shoji S, Kanazawa I: "Cell cycle arrest enhances the in vitro cellular toxicity of the truncated Machado-Jpseph disease gene product with an expanded polyglutamine stretch"Human Molelular Genetics. 9. 69-78 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Wang GH, Sawai N, Kotliarova S, Kanazawa I, Nukina N: "Ataxin 3, the MJD1 gene product, interacts with the two human homologs of yeast DNA repair protein RAD23, HHR23A and HHR23B"Human Molelular Genetics. 9. 1795-1803 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hazeki N, Tukamoto T, Goto J, Kanazawa I: "Formic acid disolves aggregates of and N-terminal huntingtin fragment containing an expanded polyglutamine tract : applying to quantification of protein components of the aggregates"Biochemical Biophysical Research Cummunications. 277. 386-393 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kanazawa I: "How do neurons die in neurodege-nerative diseases?"Trends in Molelular Medicine. 7. 339-344 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Nakamura k, Jeong SY, Uchihara T, Anno M, Nagashima K, Nagashima T, Ikeda S, Tsuji S, Kanazawa I: "SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein"Human Molelular Genetics. 10. 1441-1448 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hashida H, Goto J, Suzuki T, Jeong SY, Masuda N, Ooie T, Tachiiri Y, Tsuchiya H, Kanazawa I: "Single cell analysis of GAG repeat in brains of dentatorubral-pallidoluysian atrophy (DRPLA)"Journal of Neurological Sciences. 190. 87-93 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kanazawa I , edited by Harber P and Peruts M: "Molecular pathology of dentatorubral-pallidoluysian atrophy "Glutamine Repeats and Neurodege-nerative Diseases : Molecular Aspects""Oxford University Press. 249-260 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Y Ichikawa, J Goto, M Hattori, A Toyoda, K Ishii, SY Jeong, et al.: "The genomic structure and expression of MJD, the Machado-Joseph disease gene"Journal of Human Genetics. 46. 413-422 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] H Ishiguro, K Yamada, H Sawada, K Nishi, N Ichino, et al.: "Age-dependent and tissue-specific CAG repeat instability occurs in mouse Knock-in for a mutant Huntington's disease gene"Journal of Neuroscience Research. 65. 289-297 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] K Nakamura, SY Jeong, T Uchihara, M Anno, K Nagashima, et al.: "JC virus regulatory region rearrangements in the brain of a long surviving patients with progressive multifocal leukoencephalopathy"Human Molecular Genetics. 10・14. 1441-1448 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] H Hashida, J Goto, T Suzuki, SY Jeong, N Masuda, T Ooie, et al.: "Single cell analysis of CAG repeat in brains of dentatorubral-pallidolluysian atrophy(DRPLA)"Journal of Neurological Sciencea. 190. 87-93 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] A Iwata, M Miyake, I Kanazawa, N Nukina: "α-synuclein affects the MAPK pathway and accelerates cell death"Journal of Biological Chemistry. 276・48. 45320-45329 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] I Kanazawa: "Molecular pathology of dentatorubral-pallidoluysian atrophy"In "Glutamine repeats and neurodegenerative diseases : molecular aspects" edited by P Harper et al. Oxford University Press. 12(p.249-260) (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yoshizawa T,Yamagishi Y,Koseki N,Goto J,Yoshida H,Shibasaki F,Shoji S & Kanazawa I: "Cell cycle arrest enhances the in vitro cellular toxicity of the truncated Machado-Joseph disease gene product with an expanded polyglutamine stretch."Hum Mol Genet. 9(1). 69-78 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Jeong SY,Goto J,Hashida H,Suzuki T,Masuda N,Hirai M,Isahara K, et.al.: "Identification of a novel human voltage-gated sodium channel α subunit gene, SCN12A."Biochem Biophys Res Commun. 267. 262-270 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ogata K,Jeong SY,Murakami H,Hashida H,Suzuki T,Masuda N,Hirai M, et.al.: "Cloning and expression study of the mouose tetrodoxin-resistans voltage-gated sodium channel α subunit NaT/Scn 11a."Biochem Biophys Res Commun. 267. 271-277 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Waragai M,Jun E,Kajikawa M,Takeuchi S,Kanazawa I,Shibata M, et.al.: "PQBP-1/Npw38, a nuclear protein binding to the polyglutamine tract, interacts with U5-15kD/dim1p via the carboxyl-terminal domain."Biochem Biophys Res Commun. 273. 592-595 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Suzuki T,Nishiyama K,Yamamoto A,Inazawa J,Iwaki T,Yamada T, et al.: "Molecular cloning of a novel apoptosis-related gene, human Nap1 (NCKAP1), and its possible relation to Alzheimer disease."Genomics. 63. 246-254 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Wang GH,Sawai N,Kotliarova S,Kanazawa I & Nukina N: "Ataxin-3, the MJD1 gene product, interacts with the two human homologs of yeast DNA repair protein RAD23, HHR23A and HHR23B."Human Molecular Genetics. 9(12). 1795-1803 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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