circADAMTS6在心肌细胞电重构导致的心房颤动中的作用及机制研究

Electrical remodeling, malfunction or abnormal expression of ions channel proteins of atrial cardiomyocyte, is one of the major mechanisms in the initiation and maintainance of atrial fibrillation. Our previous circRNAs microarray data showed that circRNAs expression changed remarkably in the plasma of between health volunteers and fibrillation patents. Through bioinformatics analysis, circADAMTS6, which is the most significantly different circRNA, indirectly regulate multiple ion channel proteins expression. To further investigate the role of circRNA in the electrical remodeling induced fibrillation, the present program was designated to 1) validate the association between circADAMTS6 and atrial fibrillation with an enlarged sample size; 2) testify the originate of cicADAMTS6 in atrial cardiomyocytes, investigate the potential influence on the electrophysiology of atrial cardiomyocyte and its potential mechanism; 3) circADAMTS6 knock-down in animal model to investigate its role in electrical remodeling and influence on susceptibility to atrial fibrillation. This study is based on clinical plasma sample and designed to elucidate circRNAs mechanism with atrial fibrillation through in vitro and in vivo. Our study is aimed to find out the vital mediator in electrical remodeling induced atrial fibrillation, which would serve as a novel therapeutic target in the prevention and reversion of atrial electrical remodeling.

心房肌细胞离子通道蛋白的表达或功能异常（即心房电重构）是心房颤动发生和维持的重要机制。本项目组前期circRNA芯片研究结果显示circRNA在房颤患者与健康对照组血浆中的表达差异显著，生物信息学分析显示差异表达最显著的circADAMTS6可间接调控多个离子通道蛋白的表达从而促进心房电重构。为探讨circRNA在心房电重构引起房颤中的作用及机制，本研究将：1.在扩大的病例对照组样本中验证circADAMTS6与房颤相关性；2.验证circADAMTS6在心房肌细胞表达丰度，探索其对心房肌细胞电生理功能的影响及机制；3.动物水平敲低circADAMTS6，验证其表达变化对心房电重构及房颤易感性的影响并探索相应机制。本研究拟从上述人体标本水平、细胞水平及整体动物水平全面研究circRNAs与房颤的相关性及其作用机制，以期发现房颤的主要发病介质，为预防及逆转心房电重构提供新型治疗靶点。

项目背景：心房肌细胞离子通道蛋白的表达或功能异常（即心房电重构）是心房颤动发生和维持的重要机制。本项目组前期circRNA芯片研究结果显示circRNA在房颤患者与健康对照组血浆中的表达差异显著，生物信息学分析显示差异表达最显著的circADAMTS6可间接调控多个离子通道蛋白的表达从而促进心房电重构。.主要研究内容：本课题围绕“心肌细胞内circRNAs 可竞争性结合miRNAs，进而调控心房肌细胞内离子通道蛋白的表达和功能，最终引起心肌细胞发生电重构，增加心房颤动的易感性。”这一假说，基于本实验组前期就血浆circRNAs 与心房颤动相关性研究的初步结果，分别从细胞及动物水平研究circRNAs 在心房颤动发生中的作用及机制。主要研究内容是检测环状RNA在房颤的发生和进展中是否会异常表达；同时通过离体及在体模型探索环状RNA在房颤的发生及发展中的分子机制。.我们的研究结果提示：（1）环状RNA芯片结合生物信息学分析明确hsa_circ_0004104和hsa_circ_0001204为房颤进展的关键环状RNA；且当hsa_circ_0001204在外周血浆表达升高时，可预测阵发性房颤患者进展为持续性房颤，以及接受射频消融患者的房颤复发事件（结果尚未发表）。（2）心房成纤维细胞发生表型转化后生成的肌型成纤维细胞可能通过外泌体携带的非编码RNA（miR-21）对心房肌细胞发生影响，导致L型钙离子通道的表达下调，从而引起心房电重构，为房颤的发生和进展提供分子基质。.上述结果从分子层面提示了环状RNA及microRNA在分子层面在房颤的发生和进展中的潜在机制，增进了我们对于房颤发病基质的了解；同时，研究中验证的环状RNA有望预测阵发性房颤的进展以及房颤射频消融治疗反应性，从而有望成为一种用于辅助预后预测和治疗决策的分子标志物。.课题组发表标注国家自然基金资助SCI论文4篇，培养博士生3名。