CHIP蛋白参与脊髓小脑共济失调3型发病的分子机制及潜在治疗策略

脊髓小脑共济失调3型(SCA3)是我国最常见的神经遗传性疾病之一，深入探讨其分子病理机制及新治疗靶标是本研究领域的重大挑战。研究显示：SCA3致病蛋白Ataxin-3与泛素E3连接酶CHIP存在相互作用，Ataxin-3的PolyQ突变可导致CHIP表达降低。我们的前期工作则表明：CHIP功能缺失可直接导致小脑神经元变性死亡， 基于以上实验结果我们推测： Ataxin-3突变导致的CHIP表达下调参与了SCA3发病的分子病理过程。本课题拟进一步应用体外细胞模型、Ataxin-3/CHIP双转基因小鼠模型、SCA3患者特异iPSC模型及SCA3患者生物样本，从分子、细胞、动物模型及患者生物标记物等多方面探讨CHIP参与SCA3发病的分子机制及上调CHIP表达对SCA3的潜在治疗作用。本研究前期工作基础扎实并支持主要科学假说，实验方法完备，有望阐明SCA3新的分子病理机制并提供新的治疗靶标。

Spinocerebellar ataxia type 3 (SCA3) is one of the most common inherited neurological disorders in China, and it is a great challenge to investigate its pathogenesis and new therapeutic targets. Previous studies showed that Ataxin-3 could interact with ubiquitin E3 ligase CHIP, and mutant Ataxin-3 with PolyQ mutation could down regulate CHIP expression. In our previous work, we found that defect of CHIP could lead to the degeneration of cerebellar neurons. Based on these findings, we put forward a hypothesis that down regulation of CHIP secondary to Ataxin-3 mutation may play an important role in the pathogenesis of SCA3. In this study, we will investigate the pathogenesis of CHIP involved in SCA3 and the potential therapeutic effect of up-regulated CHIP by using the cell model, Ataxin3/CHIP double transgenic mice model, patients-specific iPSC model and biological sample of SCA3. Based on the solid previous work in accordance with the scientific hypothesis and advanced experiment methods, this study is expected to clarify new pathogenesis of SCA3 and provide new therapeutic targets.