2007 Fiscal Year Final Research Report Summary
Development of therapies in polyglutamine diseases using hepatocyte growth factor (HGF)
| Project/Area Number |
18599002
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurology
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| Research Institution | Nagoya University |
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Principal Investigator |
ADACHI Hiroaki Nagoya University, Graduate School of Medicine, Associate Professor (40432257)
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| 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)
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| Project Period (FY) |
2006 – 2007
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| Keywords | spinal and bulbar muscular atrophy / hepatocyte erowth factor / transgenic mouse / androgen receptor / CAG repeat / neurotrophic factor / muscle atrophy / muscle weakness |
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| 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.
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[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
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Journal Title
J Neurosci 27
Pages: 5115-5126
Description
「研究成果報告書概要(欧文)」より
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[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
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Journal Title
Neuropathol Appl Neurobiol 33
Pages: 135-151
Description
「研究成果報告書概要(欧文)」より
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[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
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Journal Title
J Neuropathol Exp Neurol 66
Pages: 617-627
Description
「研究成果報告書概要(欧文)」より
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[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
