肌张力障碍是以肌肉不自主收缩为特征的运动障碍病，发病机制不明确，缺乏根治手段。申请人前期建立了肌张力障碍临床队列，报道了ANO3基因多个致病性突变位点。目前，ANO3突变导致肌张力障碍的原因并不清楚。前期实验发现，ANO3蛋白在小鼠纹状体高表达，与SLACK蛋白结合；致病性突变导致ANO3蛋白水平降低；敲低细胞ANO3引起多巴胺D1受体（DRD1）通路异常。结合既往研究显示多巴胺受体通路与肌张力障碍密切相关，而SLACK互作用蛋白FMRP调节DRD1通路，我们提出本课题的科学假说：ANO3突变通过SLACK-FMRP-DRD1通路参与肌张力障碍发生。本项目将在前期基础上，通过基因敲除小鼠模型、膜片钳、免疫共沉淀、蛋白组学分析和影像学等技术，阐明ANO3突变对纹状体多巴胺受体通路的影响，明晰ANO3调节多巴胺受体通路的具体机制，以揭示肌张力障碍的发病机制，为治疗提供干预靶点。

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. The pathophysiology of dystonia remains unclear, making it hardly to be cured. We have already established a clinical cohort of dystonia and reported several novel detrimental ANO3 gene mutations for the first time.To date, the underlying pathogenesis of ANO3-induced dystonia is still unknown. Our previous experiments revealed a high expression and colocalization of ANO3 and SLACK protein in mice striatum. Pathogenic ANO3 mutation resulted in a decreased ANO3 protein level. Abnormal changes of dopamine D1 receptor (DRD1) pathway were observed in ANO3 knockdown cells. Overwhelming data suggest a strong link of dopaminergic pathways and dystonia while FMRP, a protein interacting with SLACK, regulates DRD1 pathway. Therefore, we hypothesized that SLACK-FMRP-DRD1 dysfunction is the core pathophysiology leading to dystonia induced by ANO3 mutation. Based on our previous findings, we would further study how ANO3 gene mutations affect dopamine receptor pathway in striatum by using gene knockout animal models, patch clamp, co-immunoprecipitation, proteomic analysis and neuroimaging. We aim to clarify the specific mechanism of ANO3 regulating dopamine receptor pathway in order to uncover the pathogenesis of dystonia and to provide intervention targets for treatment.