Development of pathogenesis-based therapy for polyglutamine diseases

多聚谷氨酰胺疾病的基于发病机制的治疗方法的开发

• 批准号: 17025020
• 负责人: SOBUE Gen
• 金额: $ 106.94万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2009
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17025020/
• 关键词: ポリグルタミン; 球脊髄性筋萎縮症(SBMA); 脊髄小脳失調症(SCA); 転写障害; TGF-β; 球脊髄性筋萎縮症; 運動ニューロン; ユビキチン; プロテアソーム; 17-DMAG; ポリグルタミン病; CHIP; 軸索輸送; モーター蛋白質; dnactin1; ニューロフィラメント; HSP; 17-AAG; GGA; ユビキチン-プロテアソーム

In this study, we demonstrated that the disruption of TGF-β signaling by the pathogenic androgen receptor (AR) is associated with polyglutamine-induced motor neuron damage in SBMA. Our in vivo analyses also showed that Hsp90 inhibitors facilitate proteasomal degradation of the pathogenic AR. These results indicate that pharmacological modification of UPS activity and cellular signals such as TGF-β appear to be promising therapeutic approaches for SBMA and other polyglutamine diseases.

在这项研究中，我们证明了致病性雄激素受体（AR）对TGF-β信号传导的破坏与SBMA中聚谷氨酰胺诱导的运动神经元损伤相关。我们的体内分析还表明，热休克蛋白90抑制剂促进蛋白酶体降解的致病性AR。这些结果表明，UPS活性和细胞信号（如TGF-β）的药理学修饰似乎是SBMA和其他多聚谷氨酰胺疾病的有希望的治疗方法。

项目成果

In vitro and in silico analysis reveals an efficient algorithm to predict the splicing consequences of mutations at the 5' splice sites.

• DOI: 10.1093/nar/gkm647
• 发表时间: 2007
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Sahashi K;Masuda A;Matsuura T;Shinmi J;Zhang Z;Takeshima Y;Matsuo M;Sobue G;Ohno K
• 通讯作者: Ohno K

Clinical and electrophysiologic correlates of IVIg responsiveness in CIDP

• DOI: 10.1212/01.wnl.0000158680.89323.f8
• 发表时间: 2005-04-26
• 期刊: NEUROLOGY
• 影响因子: 9.9
• 作者: Iijima, M;Yamamoto, M;Sobue, G
• 通讯作者: Sobue, G

CHIP overexpression reduces mutant androgen receptor protein and ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model

• DOI: 10.1523/jneurosci.1242-07.2007
• 发表时间: 2007-05-09
• 期刊: JOURNAL OF NEUROSCIENCE
• 影响因子: 5.3
• 作者: Adachi, Hiroaki;Waza, Masahiro;Sobue, Gen
• 通讯作者: Sobue, Gen

Usefulness of combined fractional anisotropy and apparent diffusion coefficient values for detection of involvement in multiple system atrophy

• DOI: 10.1136/jnnp.2006.104075
• 发表时间: 2007-07-01
• 期刊: JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
• 影响因子: 11
• 作者: Ito, Mizuki;Watanabe, Hirohisa;Sobue, Gen
• 通讯作者: Sobue, Gen

Intravenous immunoglobulin therapy markedly ameliorates muscle weakness and severe pain in proximal diabetic neuropathy

• DOI: 10.1136/jnnp.2006.111302
• 发表时间: 2007-08-01
• 期刊: JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
• 影响因子: 11
• 作者: Kawagashira, Y.;Watanabe, H.;Sobue, G.
• 通讯作者: Sobue, G.