DACT1调控细胞骨架引起Cx43-gap junctions重塑参与房颤的研究

心房颤动（房颤）是临床常见的持续性心律失常。我们前期研究首次发现，DACT1表达是房颤疾病中的保护因素，它可通过结合胞浆的β-catenin、增加细胞骨架累积，进而增加Cx43表达，这强烈提示DACT1可能是调控Cx43-gap junctions（Cx43-GJs）重塑的“马达分子”之一。ZO-1是Cx43与细胞骨架肌动蛋白之间的重要联系，调控Cx43-GJs重塑。本项目拟研究DACT1是否通过增加细胞骨架聚集、稳定Cx43-GJs、减少房颤易感性。本项目拟应用DACT1条件性敲除动物模型，明确心肌组织的DACT1敲除后是否增加房颤的易感性；在机制研究方面，运用心肌细胞分离纯化、免疫荧光和co-IP等分子生物学技术，明确DACT1是否影响通过细胞骨架和ZO-1调控Cx43-GJs重塑。本项目的实施将为进一步揭示房颤机制提供数据。

Atrial fibrillation (AF) is a common clinical persistent arrhythmia. Our previous study found for the first time that DACT1 expression was a protective factor in AF. It could increases cytoskeletal accumulationby binding to cytoplasmic β-catenin, resulting in increasing Cx43 expression , which strongly suggested that DACT1 may be involved in the regulation of Cx43-gap junctions ( Cx43-GJs) remodeling as a "motor molecules." ZO-1 is an important link between Cx43 and cytoskeletal actin, and regulates Cx43-GJs remodeling. This project aims is to investigate whether DACT1 can reduce the AF susceptibility by increasing cytoskeleton rearrangement and stabilizing Cx43-GJs. By using DACT1 conditional knockout animal model, we determine whether myocardial DACT1 knockout increases the AF susceptibilit. By using the molecular biology techniques such as myocardial cell isolation and purification, immunofluorescence and co-IP , we determine whether DACT1 regulates Cx43-GJs remodeling through cytoskeleton and ZO-1. The implementation of this project will provide data for further revealing the mechanism of AF.