Transcriptional regulation in the ventricular conduction system

心室传导系统的转录调节

基本信息

批准号：
10063955
负责人：
Glenn I Fishman
金额：
$ 75.53万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10063955
关键词：
Address Adult Aging Area Arrhythmia Base Pairing Biological Assay Biological Process Cardiac conduction system Cardiovascular Diseases Cardiovascular Physiology Cause of Death Cell Differentiation process Cells Cessation of life DICER1 gene Data Defect Developed Countries Development Disease Electrophysiology (science)Embryonic Heart Exposure to Female Gene Expression Profile Gene Expression Profiling Genes Genetic Transcription Health Heart Heart Abnormalities Heart Block Heart Diseases Heart failure Heritability Individual Investigation Ion Channel Knowledge Laboratories LacZ Genes Messenger RNA MicroRNAs Modeling Mus Muscle Cells Myocardial Myocardium Pathogenesis Pathologic Pattern Periodicity Physiology Play Population Publishing Purkinje Cells Regulator Genes Reporter Research Role Syndrome System Systems Biology Systems Development Testing Transcript Transcriptional Regulation Translations United States Untranslated RNA Ventricular bioinformatics pipeline clinically relevant comparative differential expression experimental study functional genomics genetic regulatory protein heart rhythm inhibitor/antagonist loss of function male mouse Cre recombinase novel patch clamp postnatal pressure progenitor response sex stem cell differentiation stem cells stressor sudden cardiac death transcription factor virtual

项目摘要

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.

项目概要心室传导系统（VCS）对于正常的心肌兴奋和兴奋至关重要。收缩。扰乱 VCS 形成或功能的遗传性和获得性综合征是导致心血管疾病的巨大负担，包括心脏传导阻滞、触发性心律失常和折返性心律失常，心源性猝死，以及心肌不同步和心力衰竭的进展。利用基因编码传导系统报告小鼠、比较转录谱和一系列功能我们的实验室在 VCS 发育、生理学和疾病发病机制的研究方面处于领先地位。通过这种方法，我们鉴定并表征了浦肯野细胞的转录特征，确定了许多调节 VCS 生物学各个方面的新基因，包括转录因子，离子通道亚基和调节蛋白。在当前的申请中，我们建议建立一个更加全球化的以及对在这一罕见群体中发挥作用的基因调控网络的全面了解通过将我们的分析扩展到包括 VCS 中差异表达的 microRNA，可兴奋细胞。更具体地说，我们建议：确定 VCS 中 microRNA 的细胞自主需求；使用功能基因组学筛选鉴定浦肯野细胞分化所需的 microRNA；并定义健康和疾病中的浦肯野细胞转录特征和电生理学。