NUP155通过转录因子NKX2.5调控HCN4和KCNQ1诱发房颤机理研究

房颤是最常见的心律失常，会导致心衰和猝死，并具有高致残性和致死性，其遗传机制有待进一步阐明。NUP155纯合突变R391H会导致房颤，但其分子机制仍不清楚。预实验发现在斑马鱼中敲低nup155导致：nkx2.5表达下降并影响心脏结构；hcn4表达升高并使心率升高；kcnq1表达升高并使动作电位APD90缩短。同时前期转录组学分析表明HL-1细胞中Nkx2.5调控房颤相关基因Hcn4和Kcnq1表达,这与已有研究结果一致。本课题拟使用已建立的nup155-/-斑马鱼模型和HL-1细胞，从动物到分子多个层面验证科学假说：NUP155通过NKX2.5间接调控HCN4和KCNQ1的表达，影响心脏结构以及电生理活动，最终影响房颤发生。本项目有望揭示NUP155导致房颤的分子机制，提升对房颤发病机理的认识，为房颤的预防和治疗提供理论基础。

As the most common arrhythmia disease, atrial fibrillation can cause heart failure and sudden death and has a high mutilation and fatality rate, but the genetic and molecular mechanism of atrial fibrillation needs further elucidation. NUP155 homozygous mutation R391H can give rise to atrial fibrillation. However, the underlining mechanism remains unclear. The results from preliminary experiments showed that nup155 knockdown in zebrafish embryos downregulates the expression of nkx2.5 and influences the heart structure. While the expressions of hcn4 and kcnq1 are upregulated, significantly elevated heart rate and shortened action potential APD90 of atrial cells were detected. Transcriptome data indicate that Nkx2.5 modulates the expression of atrial fibrillation relevant gene, Hcn4, and Kcnq1 in HL-1 cells. Previous reports have shown that knockdown of nkx2.5 in HL-1 cells upregulates the expression of hcn4. Furthermore, nkx2.5 regulates potassium current in P19CL6 cells. By using the established nup155 knockout zebrafish, we aim to validate the hypothesis from animal to molecule level: NUP155 mutation can cause increased HCX4 and KCNQ1 expression through decreased NKX2.5 expression, following the abnormal k+ current in cell membrane, altered electrophysiology and structure of the heart, and eventually atrial fibrillation. This study may unravel the function and mechanism of NUP155 in atrial fibrillation and improve our current understanding of the pathogenesis of atrial fibrillation, providing the theoretical fundament for the prevention and treatment of atrial fibrillation.