遗传性共济失调是一组以共济失调为主要表现的神经系统罕见遗传病，深入探讨其发病机制及新治疗靶标是罕见病领域的重大挑战。在前期工作中，申请人首次在国际上报道了CHIP编码基因突变可导致遗传性共济失调综合征的发生，并在前期工作中构建了CHIP相关共济失调动物模型。在进一步研究中发现：该模型中神经系统PDE9A表达水平显著增加，且其表达量与疾病进展相关，在体外实验中首次发现CHIP与PDE9A存在相互作用。基于以上结果我们推测，PDE9A及其调控的cGMP信号通路可能参与了CHIP相关遗传性共济失调的发生，靶向PDE9A可能是CHIP相关共济失调的新治疗靶点。本课题拟进一步在体外细胞模型、CHIP突变动物模型中探索CHIP与PDE9A二者的相互作用关系及靶向PDE9A治疗对CHIP相关共济失调的潜在神经保护作用，本研究有望进一步揭示遗传性共济失调新的疾病机制并建立新的治疗策略，具有重要意义。

Hereditary ataxia is a group of rare neurogenetic diseases characterized by ataxia. In-depth study of its pathogenesis and new therapeutic targets is a major challenge in the field of rare diseases. The applicant reported mutation in CHIP could lead to hereditary ataxia syndrome for the first time, and constructed a new animal model of CHIP-related ataxia in the preliminary work. Further research showed that, the expression of PDE9A in nervous system was significantly increased in this model, and the expression level was related to disease progression. We also confirmed the interaction between CHIP and PDE9A in vitro for the first time. Given these results, we hypothesized that PDE9A and its regulated cGMP signaling pathway may involve in the pathogenesis of CHIP-related hereditary ataxia, and targeting PDE9A could be a new treatment method for the disease. This study intends to explore the interaction between CHIP and PDE9A and the potential neuroprotective effect of targeting PDE9A in both cell and CHIP-mutation animal model. This study is expected to reveal the new pathogenesis of hereditary ataxia and establish the new treatment strategy and has great scientific significance.