药源性长QT综合征：hERG抑制剂诱导的转录后调控网络

The hERG potassium channel inhibitor is the main cause of drug-induced long QT syndrome (LQTS), and it is a significant issue to investigate its mechanism and to develop effective biomarkers for avoiding sudden cardiac death induced by LQTS.This project from the perspective of the whole genome for the first time, explores the miRNA mediated post-transcriptional regulatory mechanism which is induced by hERG inhibitor，to explain the mechanism of drug-induced LQTS，and will provide potential biomarkers of drug-induced LQTS. The project will combine mRNA and miRNA expression profiling, miRNA-target gene relationship, the transcription factor-miRNA relationship, biological pathways and other data resources, and apply bioinformatics method to high-throughput screen specific activated miRNAs and their regulatory pathways in the post-transcriptional regulatory system induced by hERG inhibitor, and assess the riskiness of these drug-induced LQTS related miRNAs, part results of which will be further validated by biological experiments. The study is to elucidate the molecular mechanisms of the drug-induced LQTS, and to provide the source of innovative work for the development of effective biomarkers in screening the patients with high-risk drug-induced LQTS.

hERG钾通道抑制剂是药源性长QT综合征(LQTS)的主要诱因,探讨LQTS发生机制并开发有效生物学标记,从而防治心源性猝死的发生具有重要意义。本项目从全基因组的角度，探索hERG抑制剂诱导的miNRA转录后调控机制，解释药源性LQTS的发生机理，提供潜在的早期诊断LQTS生物学标记。项目整合 mRNA和miRNA表达谱、miRNA-靶基因关系、转录因子-miRNA关系、生物学通路等数据资源，应用生物信息学方法筛选转录后调控系统中药源性LQTS特异激活的miRNA以及其调控的通路，对这些风险miRNA进行优先级评估，并将结果进行生物学证实。该项研究预期结果将进一步阐明药源性LQTS发生的分子机制，助推LQTS生物标记的研发，为筛查高风险药源性LQTS病患提供源头创新性工作。

hERG钾通道抑制剂是药源性长QT综合征(LQTS)的主要诱因,探讨LQTS发生机制并开发有效生物学标记,从而防治心源性猝死的发生具有重要意义。近年来，抑制hERG表达的机制研究逐渐成为热点。本项目开发了一种发现hERG表达障碍特异的TF-Gene-microRNA风险复合调控网络的计算框架。首先，建立三氧化二砷、盐酸小檗碱、普罗布考诱发hERG转运障碍时的差异表达基因网络，并用MCODE挖掘网络模块，同时应用超几何检验建立差异表达转录因子和microRNA分别与模块的富集关系；然后，计算两两网络中显著交互的模块对，并基于此，构建三元互作模块环，经大鼠心脏组织毒性数据和ROC曲线筛选获得核心三元模块环；最后融合核心三元模块环与TF、microRNA构建风险复合调控网络。大鼠数据显示基于差异表达基因的三元互作模块环与hERG表达障碍密切相关，风险复合调控网络由272个基因、68个microRNA和14个转录因子构成，网络中度高节点具有高风险，为药源性LQTS的发生机理提供了一些新的见解。