高同型半胱氨酸（Hcy）与房颤和房颤消融术后复发呈显著正相关，但机制尚不清楚。我们既往的研究发现，转录因子TBX5基因突变可导致房颤；高Hcy可使TBX5蛋白表达增加。因此，本研究提出假说，高Hcy可能通过TBX5及下游调控的靶基因参与房颤的发生发展。本课题拟：1）通过转录组测序确定高Hcy和TBX5共同调控的下游基因，经信息学分析初步确定可能参与房颤的候选基因。2）通过siRNA技术和心房肌细胞电生理检测，筛选出对动作电位时程影响最显著的候选基因作为目的基因。3）通过CRISPR/Cas9技术构建目的基因小鼠模型，分别从在体动物、心房肌细胞层面阐明高Hcy导致房颤的机制。本研究将论证“Hcy—TBX5—目的基因—离子通道—心房颤动”的信号通路和分子机制，为高Hcy相关房颤的临床防治提供新的思路。

Elevated homocysteine (Hcy) is significantly associated with atrial fibrillation (AF) and AF recurrence after ablation, however, the detailed mechanisms are still unclear. Our previous study found that the mutation of TBX5 gene could cause AF, and the protein expression of TBX5 was increased under high concentration of Hcy. Herein, the hypothesis is raised that elevated Hcy may lead to the development of AF through TBX5 and its downstream genes. The present study is aimed to: 1) perform mRNA sequencing to determine the downstream genes regulated by high Hcy and TBX5, and identify the candidate genes by bioinformatic analysis. 2) confirm target genes which have the most significant effect on action potential duration using siRNA and cardiac electrophysiological examination. 3) create mice model by CRISPR/Cas9 method and clarify the mechanism underlying high Hcy and AF. The study will illustrate the “homocysteine-TBX5-target gene-ion channel-AF” pathway and the molecular mechanism, providing new theoretical basis for high Hcy associated AF management.