病窦综合症是心律失常单独发病的代表性疾病，国外学者及申请人发现POPDC跨膜家族基因与该疾病的发生有关，但发病分子机制不明。申请人利用鼠心肌细胞与斑马鱼基因敲除模型，证明POPDC3膜蛋白不通过经典的受体介导信号传导，而是由新合成的跨膜蛋白直接入核调控心脏的功能，进而提出POPDC3以“先核定位策略”调控病窦综合症发生的假设。申请人拟利用斑马鱼和小鼠模型结合病窦综合症患者材料，研究核内POPDC3蛋白突变导致病窦综合症发生的表型，其是否通过互作蛋白ATF4入核并协同调控疾病的发生，以及两者是否通过靶基因GATA4-Cx30.2信号通路调控病窦综合症的发生，从而阐明POPDC3蛋白调控病窦综合症发生的分子病理机制，为临床治疗病窦综合症提供指导。

Sick sinus syndrome（SSS）is the representative disease of arrhythmia. Foreign scholars and the applicant find that POPDC transmembrane gene family is associated with the disease, but the molecular mechanism is unknown. By zebrafish gene knockout model and rat and mouse cardiac cell models, the applicant show that POPDC3 regulates heart development via the new synthesyned transmembrane protein directly entering the nucleus, rather classic receptor transduction pathway, making a hypothesis that POPDC3 persures a first nuclear localization stretage for SSS. Using zebrfish and mouse gene knockout and the sick gene mutation knockin mouse models, the applicant will study the sick phenotype of POPDC3 entering nucleus via its interacting protein ATF4 and their tagets GATA4-Cx30.2 signaling, elucidating the molecular mechanism of the gene mutation with SSS, which will provide guidance for the clinical treatment of SSS.