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.

项目摘要心室传导系统（VCS）对于正常的心肌激发至关重要收缩。可遗传和获得的综合症干扰VCS形成或功能是为了心血管疾病的重大负担，包括心脏障碍，触发和重入心律失常，心脏猝死以及心肌障碍和心力衰竭进展。使用遗传编码的传导系统记者小鼠，比较转录分析和一系列功能测定法，我们的实验室已经开创了VCS发育，生理和疾病发病机理的研究。通过这种方法，我们已经确定并表征了Purkinje细胞和确定了许多调节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。在当前的应用程序中，我们建议建立一个更全球的以及对在这种罕见人群中运作的基因调节网络的全面了解通过扩展我们的分析以包括在VC中差异表达的microRNA，通过扩展分析。更具体地说，我们建议：确定VC中microRNA的细胞自主要求；使用功能基因组筛选来确定Purkinje细胞分化所需的microRNA；并定义 Purkinje细胞转录特征和健康和疾病中的电生理学。