| Project/Area Number |
12210010
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | Nagoya University |
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Principal Investigator |
SOBUE Gen Nagoya Univesity, Department of Neurology, Professor, 大学院医学系研究科, 教授 (20148315)
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| Co-Investigator(Kenkyū-buntansha) |
DOYU Manabu Nagoya Univesity, Department of Neurology, Assistant Professor, 大学院医学系研究科, 助教授 (90293703)
INUKAI Akira Nagoya Univesity, Department of Neurology, Lecturer, 医学部附属病院, 講師 (30314016)
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| Project Period (FY) |
2000 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥108,900,000 (Direct Cost: ¥108,900,000)
Fiscal Year 2004: ¥26,400,000 (Direct Cost: ¥26,400,000)
Fiscal Year 2003: ¥26,400,000 (Direct Cost: ¥26,400,000)
Fiscal Year 2002: ¥26,400,000 (Direct Cost: ¥26,400,000)
Fiscal Year 2001: ¥29,700,000 (Direct Cost: ¥29,700,000)
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| Keywords | neurodegeneration / motor neuron / polyglutamine / andorogen receptor / LHRH analog / histone / heat shock protein / アロドロゲン受容体 / geranylgeranylaceone / 球脊髄性筋萎縮症 / CAGリピート / トランスジェニックマウス / 去勢術 / HSP70 / びまん性核内蓄積 / テストステロン / ホルモン治療 / Hsp / CAGリピート病 / ポリグルタミン鎖 / 神経細胞死 / アデノウイルスベクター / 培養神経系細胞モデル / DNA chip / 遺伝子発現解析 / 球脊髄性筋萎縮症(SBMA) / アンドロゲン受容体(AR) / レーザーマイクロダイセクション法 / cDNAマイクロアレー |
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| Research Abstract |
Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease affecting only males. The molecular basis of SBMA is the expansion of a trinucleotide CAG repeat in the first exon of the androgen receptor (AR) gene, which encodes the polyglutamine (polyQ) tract. The length of CAG repeat correlates with the severity of SBMA. Immunohistochemical analysis of autopsied specimen demonstrates that diffuse accumulation of mutant AR in the nuclei of spinal motor neurons is a fundamental neuropathological feature of SBMA, extent of which closely relates to CAG repeat length. Thus, diffuse nuclear accumulation of mutant AR is likely crucial pathogenic step in SBMA. We generated two mouse models of SBMA. Among these, a transgenic mouse model carrying full-length AR containing 97 CAGs driven by a chicken (3-actin promoter shows progressive motor impairment and nuclear accumulation of mutant AR. These neurological phenotypes were devastating in male mice, but not observed or far less severe in the females. Surgical castration dramatically prevented the phenotypic expression in the male Tg mice by diminishing the nuclear accumulation of mutant AR. In contrast, the female Tg mice demonstrated striking deterioration of symptoms by testosterone administration. Leuprorelin, an LHRH agonist that reduces testosterone release from the testis, suppressed nuclear accumulation of mutant AR, leading to rescue of motor dysfunction in the male SBMA mice. Our studies have also indicated several candidates of therapeutics for SBMA. Genetic overexpression of heat shock protein (HSP) ameliorates neurodegeneration by improving conformational alteration of mutant AR in the mouse model of SBMA. Oral administration of sodium butyrate, a histone deacetylase inhibitor, resulted in improvement of neurological dysfunction in the SBMA mouse model, al though its therapeutic effects were seen in a narrow dose range.
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