Basic Research for Development of Novel Therapeutics of Polyglutamine Diseases through Transcriptional Regulation

通过转录调控开发多聚谷氨酰胺疾病新疗法的基础研究

• 批准号: 16390249
• 负责人: OKAZAWA Hitoshi
• 金额: $ 7.17万
• 依托单位: TOKYO MEDICAL AND DENTAL UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390249/
• 关键词: transcription; neuron; polyglutamine; cell death; hsp70; proteome; transcriptome; neurodegeneration; 転写障害; PQBP1; Hsp70; ペプチド; BrU

In this study, we investigated changes of gene expression profiles by transcriptome and proteome analyses. We have found multiple candidate genes whose expression changes in specific types of neurons affected in polyQ diseases. Among them, we currently focus on hsp70 whose expression was dramatically up-regulated instriatal neurons by mutant huntingtin expression but not by mutant ataxin-1. The remarkable increase was not observed in other types of neurons such as granule cells or cortical neurons. We further analyzed molecular mechanisms underlying transcriptional upregulation, and found that HSF1, a famous transcription factor affecting expression of heat shock proteins, is not involve in the upregulation by mutant htt. Instead, we found another transcription factor p53 is critically involved in the regulation of hsp70 expression.We plan to use the result for developing nove therapeutics in the future.

在这项研究中，我们通过转录组和蛋白质组分析来研究基因表达谱的变化。我们已经发现了多个候选基因，它们在受PolyQ病影响的特定类型的神经元中表达变化。其中，我们目前关注的是HSP70，它的表达被突变的Huntingtin表达显著上调，而不是被突变的ataxin-1上调。其他类型的神经元如颗粒细胞或皮质神经元未见明显增加。我们进一步分析了转录上调的分子机制，发现HSF1是一个著名的影响热休克蛋白表达的转录因子，它不参与突变的HTT的上调。相反，我们发现另一种转录因子P53在HSP70表达的调节中起关键作用。我们计划在未来利用这一结果开发新的疗法。

项目成果

General transcriptional repression by polyglutamine disease proteins is not directly linked to the presence of inclusion bodies

• DOI: 10.1016/j.bbrc.2003.11.086
• 发表时间: 2004-01-02
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Hoshino, M;Tagawa, K;Okazawa, H
• 通讯作者: Okazawa, H

Oct-3/4 repression accelerates differentiation of neural progenitor cells in vitro and in vivo

• DOI: 10.1016/j.molbrainres.2004.08.021
• 发表时间: 2004-12-06
• 期刊: MOLECULAR BRAIN RESEARCH
• 作者: Okuda, T;Tagawa, K;Okazawa, H
• 通讯作者: Okazawa, H

Preventive or therapeutic agent for neurological disorder.

神经障碍的预防剂或治疗剂。

• 发表时间: 2006

Distinct aggregation and cell death patterns among different types of primary neurons induced by mutant huntingtin protein

• DOI: 10.1111/j.1471-4159.2004.02372.x
• 发表时间: 2004-05
• 期刊: Journal of Neurochemistry
• 影响因子: 4.7
• 作者: K. Tagawa;M. Hoshino;T. Okuda;H. Ueda;H. Hayashi;S. Engemann;H. Okado;M. Ichikawa;E. Wanker;H. Okazawa

Cystathionine b-synthetase, a key enzyme for homocysteine metabolism, is preferentially expressed in the radical glia/astrocyte lineage of developing mouse CNS.

胱硫醚 b-合成酶是同型半胱氨酸代谢的关键酶，优先在发育中的小鼠中枢神经系统的自由基胶质细胞/星形胶质细胞谱系中表达。

• 发表时间: 2005
• 期刊: FASEB Journal 19
• 作者: Kuwahata M;Kuramoto Y;Tomoe Y;Sugata E;Segawa H;Ito M;Oka T;Miyamoto K.;Ito M;Miyamoto K;Sagawa H;Takeda E;Segawa H;Kuwahara M;Saito H;宮本賢一;宮本賢一;Hoshino M. et al.;Enokido Y. et al.
• 通讯作者: Enokido Y. et al.