aLQTS所致TdP是院内心源性猝死的重要原因之一，其中药物导致的aLQTS 最常见。药物阻滞hERG编码的Ikr是其重要发病机制。目前hERG上游调控在药物aLQTS的作用机制尚未见相关报道。研究组以miRNA和hERG关联性为切入点，已筛选出4个hERG相关miRNA。前期研究显示miRNA在 HEK细胞中可以负向调控hERG基因表达。本课题拟研究miRNA在HEK细胞中对IKr的电流特性影响，并在乳兔心肌细胞中探讨miR-103a-1、3619对ERG功能的调控作用，初步揭示miRNA对hERG功能调控的机制；明确miRNA是否参与了aLQTS的发病，分析循环miRNA作为监测aLQTS伴TdP的生物标记物的可能；开展miRNA上游转录因子的预测与鉴定，阐明miRNA表达的转录调控机制。以期探讨miRNA在药物aLQTS的作用和机制，为其早期诊断和防治提供实验依据。

Cardiac arrest due to torsade de pointes (TdP) in the acquired form of drug-induced long-QT syndrome (LQTS) is potentially catastrophic event in hospital settings. Most drugs that cause this are thought to directly block a specific cardiac ion channel (hERG) that carries the rapidly activating delayed rectifier potassium current, IKr. However, the mechanism of the hERG gene upstream regulation in the drug-induced aLQTS has not been reported. Our research group is going to explore the relationship between abnormal expression of miRNA and the functionality change of hERG. 4 hERG related of miRNAs have been selected by luciferase reporter assay. Preliminary studies displayed that 4 miRNAs could decrease the expression hERG mRNA and protein by RT-PCR and western blot in HEK-hERG cells. This project will study influence of IKr characteristics by 4 miRNAs in HEK cells and the influence on hERG gene expression and IKr characteristics of miR-103, 3619 in rabbit cardiomyocytes. The expression level of differentially expressed microRNA was evaluated by qRT-PCR . Protein expression and subcellular localization were analyzed by western blotting and Confocal laser scanning microscope. The effect of miRNAs on the electrophysiological characteristics of the Ikr current was asseses by Patch-clamp technique. Since many studies demonstrated that serum levels of a tumor-expressed miRNA can distinguish patients with cancer from healthy controls, we will investigate the effect of hERG related miRNAs in aLQTS. Our aim is to establish the measurement of HERG related miRNAs in serum or plasma as an important circulating biomarkers detection of aLQTS. Furthermore we will carry out the prediction and identification of miRNA upstream transcription factor to clarify the mechanism of transcriptional regulation of miRNA expression. ?????.