Transcriptional regulation in the ventricular conduction system

项目总结 心室传导系统(VCS)对于正常的心肌兴奋和 收缩。遗传性和获得性综合征扰乱VCS的形成或功能负责 心血管疾病的沉重负担，包括心脏传导阻滞、触发和折返性心律失常， 心源性猝死，以及心肌不同步和心力衰竭进展。从基因上使用 编码传导系统报告小鼠，比较转录图谱，和一组功能 在化验方面，我们的实验室在VCS的发展、生理和疾病发病机制方面具有开创性的研究。 通过这种方法，我们已经鉴定和表征了浦肯野细胞的转录特征和 确定了一些新的基因来调节VCS生物学的不同方面，包括转录因子， 离子通道亚基和调节蛋白。在目前的应用中，我们建议建立一个更全球化的 以及对基因调控网络的全面了解，这些网络在这个罕见的人群中发挥作用 通过将我们的分析扩展到包括在VCS中差异表达的microRNAs，来研究可兴奋的细胞。 更具体地说，我们建议：确定VCS中对microRNAs的细胞自主需求； 利用功能基因组学筛选确定浦肯野细胞分化所需的microRNAs； 蒲肯野细胞转录特征和电生理学在健康和疾病中的作用。

PROJECT SUMMARY The ventricular conduction system (VCS) is critically important for normal myocardial excitation and contraction. Heritable and acquired syndromes perturbing VCS formation or function are responsible for a substantial burden of cardiovascular disease, including heart block, triggered and reentrant arrhythmias, sudden cardiac death, as well as myocardial dyssynchrony and progression of heart failure. Using genetically encoded conduction system reporter mice, comparative transcriptional profiling, and a battery of functional assays, our laboratory has pioneered studies of VCS development, physiology and disease pathogenesis. Through this approach, we have identified and characterized the transcriptional signature of Purkinje cells and identified a number of novel genes that regulate diverse aspects of VCS biology, including transcription factors, ion channel subunits and regulatory proteins. In the current application, we propose to establish a more global and comprehensive understanding of gene regulatory networks that are operative in this rare population of excitable cells, by extending our analysis to include microRNAs that are differentially expressed in the VCS. More specifically, we propose to: determine the cell autonomous requirements for microRNAs in the VCS; identify microRNAs required for Purkinje cell differentiation using functional genomics screens; and define Purkinje cell transcriptional signatures and electrophysiology in health and disease.