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Development of therapies in polyglutamine diseases using hepatocyte growth factor (HGF)

Research Project

Project/Area Number 18599002
Research Category

Grant-in-Aid for Scientific Research (C)

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

Principal Investigator

ADACHI Hiroaki  Nagoya University, Graduate School of Medicine, Associate Professor (40432257)

Co-Investigator(Kenkyū-buntansha) SOBUE Gen  Nagoya University, Graduate School of Medicine, Professor (20148315)
TANAKA Fumiaki  Nagoya University, Graduate School of Medicine, Assistant Professor (30378012)
FUNAKOSHI Hiroshi  Osaka University, Graduate School of Medicine, Associate Professor (40273685)
Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥3,560,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2007: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2006: ¥2,000,000 (Direct Cost: ¥2,000,000)
Keywordsspinal and bulbar muscular atrophy / hepatocyte erowth factor / transgenic mouse / androgen receptor / CAG repeat / neurotrophic factor / muscle atrophy / muscle weakness / ドランスジェニックマウス / ダブルトランスジェニックマウス
Research Abstract

Spinal and bulbar muscular atrophy(SBMA) is an inherited motor neuron disease. The molecular basis of SBMA is the expansion of a trinucleotide CAG repeat, which encodes the polyglutamine(polyQ) tract, in the androgen receptor(Alt) gene. We generated transgenic mouse model expressing the full-length human AR containing either 24 or 97 CAG repeats under the control of a cytomegalovirus enhancer and a chicken β-actin promoter(AR-97Q mice). Hepatocyte growth factor(HGF) was initially identified and molecularly cloned as a potent mitogen for mature hepatocytes. Subsequent studies revealed that HGF exerts multiple biological effects, including mitogenic, motogenic, morphogenic, and anti-apoptotic activities in a wide variety of cells, including neurons, by binding to the c-Met receptor tyrosine kinase(c-Met). HGF is one of the most potent in vitro and in vivo survival-promoting factors for neurons. For example, neurotrophic effects of HGF have been demonstrated in cultured hippocampal neurons and in cultured embryonic spinal motoneurons, and its anti-apoptotic activity in motoneurons is comparable to that of glial cell line-derived neurotrophic factor(GDNF). In the present study, the effects of HGF on motor dysfunction were examined using double transgenic mice overexpressing mutated human AR and HGF. We cross-bred AR-97Q mice with mice over-expressing the HGF. The double transgenic mice showed improvement of their motor function, body weight, lifespan. Overexpression of HDF also ameliorated motor function in the castrated male AR-97Q mice. These findings suggest that HGF over-expression ameliorates SBMA phenotypes in mice.

Report

(3 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report
  • Research Products

    (15 results)

All 2007 2006

All Journal Article (13 results) (of which Peer Reviewed: 4 results) Presentation (2 results)

  • [Journal Article] CHIP overexpression reduces the mutant AR protein and amelio rates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model.2007

    • Author(s)
      Adachi H, et. al.
    • Journal Title

      J Neurosci 27

      Pages: 5115-5126

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Pathogenesis and molecular targeted therapy of spinal and bulbar muscular atrophy.2007

    • Author(s)
      Adachi H, et. al.
    • Journal Title

      Neuropathol Appl Neurobiol 33

      Pages: 135-151

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Gene Expressions Specifically Detected in Motor Neurons(Dynactin 1, Early Growth Response 3, Acety1-CoA Transporter, Death Receptor 5, and Cyclin C)Differentially Correlate to Pathologic Markers in Sporadic Amyotrophic Lateral Sclerosis.2007

    • Author(s)
      Jiang YM, et. al.
    • Journal Title

      J Neuropathol Exp Neurol 66

      Pages: 617-627

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] CHIP overexpression reduces the mutant AR protein and ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model2007

    • Author(s)
      Adachi, H, Waza, M, Tokui, K, Katsuno, M, Minamiyama, M, Tanaka, F, Doyu, M, Sobue, G
    • Journal Title

      J Neurosci 27

      Pages: 5115-5126

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Pathogenesis and molecular targeted therapy of spinal and bulbar muscular atrophy2007

    • Author(s)
      Adachi, H, Waza, M, Katsuno, M, Tanaka, F, Doyu, M, Sobue, G
    • Journal Title

      Neuropathol Appl Neurobiol 33

      Pages: 135-151

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Gene Expressions Specifically Detected in Motor Neurons (Dynactin, 1, Early Growth Response 3, Acetyl-CoA Transporter, Death Receptor 5, and Cyclin C) Differentially Correlate to Pathologic Markers in Sporadic Amyotrophic Lateral Sclerosis2007

    • Author(s)
      Jiang, YM, Yamamoto, M, Tanaka, F, Ishigaki, S, Katsuno, M, Adachi, H, Doyu M, Yoshida, M, Hashizume, Y, Sobue, G
    • Journal Title

      J Neuropathol Exp Neurol 66

      Pages: 617-627

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Gene Expressions Specifically Detected in Motor Neurons (Dynactin 1, Early Growth Response 3, Acetyl-CoA Transporter, Death Receptor 5, and Cyclin C) Differentially Correlate to Pathologic Markers in Sporadic Amyotrophic Lateral Sclerosis.2007

    • Author(s)
      Jiang YM, et. al.
    • Journal Title

      J Neuropathol Exp Neurol 66

      Pages: 617-627

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mutant androgen receptor accumulation in SBMA scrotal skin : A pathogenic marker.2006

    • Author(s)
      Banno H
    • Journal Title

      Ann Neurol 59

      Pages: 520-526

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Pathogenesis, animal models and therapeutics in Spinal and bulbar muscular atrophy (SBMA).2006

    • Author(s)
      Katsuno M
    • Journal Title

      Exp Neurol 200

      Pages: 8-18

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Modulation of Hsp90 function in neurodegenerative disorders : a molecular-targeted therapy against disease-causing protein.2006

    • Author(s)
      Waza M
    • Journal Title

      J Mol Med 84

      Pages: 635-646

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Alleviating Neurodegeneration by an Anticancer Agent : An Hsp90 Inhibitor (17-AAG)2006

    • Author(s)
      Waza M
    • Journal Title

      Ann N Y Acad Sci 1086

      Pages: 21-34

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Reversible disruption of dynactin 1-mediated retrograde axonal transport in polyglutamine-induced motor neuron degeneration.2006

    • Author(s)
      Katsuno M
    • Journal Title

      J Neurosci 26

      Pages: 12106-12117

    • Related Report
      2006 Annual Research Report
  • [Journal Article] 臨床医のための神経病理 球脊髄性筋萎縮症2006

    • Author(s)
      足立弘明
    • Journal Title

      Clinical Neuroscience 24

      Pages: 974-975

    • Related Report
      2006 Annual Research Report
  • [Presentation] 球脊髄性筋萎縮症モデルにおけるシャペロン依存性ユビキチンリガーゼ高発現の効果2007

    • Author(s)
      足立弘明, ら
    • Organizer
      第48回日本神経学会総会
    • Place of Presentation
      名古屋
    • Year and Date
      2007-05-17
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
  • [Presentation] CHIP over-expression reduces the mutant AR protein and ameliorates phenotypes of the SBMA transgenic mouse model2007

    • Author(s)
      Adachi, H, Waza, M, Tokui, K, Katsuno, M, Minamiyama, M. Tanaka, F, Sobue, G
    • Organizer
      The 49th Annual Meeting of the Japanese Society of Neurology
    • Place of Presentation
      Nagoya
    • Year and Date
      2007-05-17
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary

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Published: 2006-04-01   Modified: 2016-04-21  

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