A Novel Role for NFATC1 in Modulating Cardiac Excitability

NFATC1 在调节心脏兴奋性中的新作用

基本信息

批准号：
10653775
负责人：
MARTIN TRISTANI-FIROUZI
金额：
$ 72.27万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10653775
关键词：
Abbreviations Action Potentials Adolescent Affinity Algorithms Animal Model Anti-Arrhythmia Agents Arrhythmia Atrial Fibrillation Binding Binding Sites Biochemical Bioinformatics Biological Assay Cardiac Cardiac Electrophysiologic Techniques Cardiac ablation Cardiovascular Diseases Cell Culture Techniques Cell Line Cells ChIP-seq Custom DNA Binding Data Economic Burden Electrophysiology (science)Enzyme-Linked Immunosorbent Assay Evolution Familial atrial fibrillation Family Fishes Foundations Functional disorder Future Gene Expression General Population Genes Genetic Transcription Genome Goals Health Care Costs Heart Heart Atrium Heart Hypertrophy Human Human Genetics Individual Ion Channel Isoproterenol Location Luciferases Mass Spectrum Analysis Measurement Measures Mediating Methodology Modality Modeling Molecular Muscle Cells Mutation Nature Nuclear Translocation Optics Pathogenesis Pathogenicity Pathologic Pathway interactions Patients Penetrance Phenotype Predisposition Property Recovery Refractory Reporter Repression Risk Role Siblings Signal Pathway Sinus Site Sudden Death Susceptibility Gene Tachyarrhythmias Techniques Testing Transcriptional Activation Transgenic Organisms Utah Variant Zebrafish bioinformatics tool cardiogenesis clinical practice design differential expression disease phenotype exome sequencing experience gene network genetic pedigree genome editing genome wide association study high risk improved in silico induced pluripotent stem cell derived cardiomyocytes innovation insight mutant mutation carrier next generation sequencing novel overexpression rare variant response risk stratification segregation single-cell RNA sequencing standard care stroke risk transcription factor transcriptome sequencing

项目摘要

PROJECT SUMMARY / ABSTRACT The overall goal of this proposal is to explore the molecular and electrophysiological role of NFATC1 as a novel atrial fibrillation (AF) susceptibility gene and to define the previously unknown contribution of NFATC1 to atrial excitability. AF, the most common sustained arrhythmia encountered in clinical practice, has an economic burden exceeding $7 billion in annual health care costs. Emerging evidence implicates cardiac transcription factors in the pathogenesis in both familial forms of AF and AF in the general population. We identified a mutation in the cardiac transcription factor NFATC1 in a high-risk Utah pedigree defined by young onset AF. NFATC1 is a Ca2+- dependent transcription factor postulated to play a role in cardiac development, but up until now has never been associated with cardiac excitability. Our exciting preliminary data identify a novel role for NFATC1 in modulating atrial excitability, in that nfatc1 null zebrafish develop spontaneous atrial tachyarrhythmia and juvenile sudden death. Aim 1 seeks to define the biochemical, molecular and electrophysiological basis of the mutant NFATC1 dysfunction, using the HL-1 atrial cell line, a human cell culture model (patient-specific and genome-edited induced pluripotent stem cell derived cardiomyocytes, iPSC-CMs), and a whole animal model (transgenic zebrafish). Aim 2 characterizes the role of NFATC1 in modulating atrial excitability by exploring the molecular and electrophysiological basis for the atrial tachyarrhythmia in nfatc1 null zebrafish. Aim 3 will define NFATC1- controlled transcriptional networks and gene pathways that regulate cardiac excitability, using single-cell RNA- Seq, ChIP-Seq and ChIP-Mass Spectroscopy in human atrium and NFATC1 null and WT iPSC-CMs. Our proposal leverages human genetics, genome-editing techniques, state-of-the-art Next-Gen sequencing modalities and bioinformatics, and electrophysiology to comprehensively characterize the novel role of NFATC1 in cardiac excitability and AF pathogenesis. An understanding of a key transcriptional network that regulates ion channel gene expression and atrial excitability will provide a broader, and more comprehensive understanding of arrhythmia susceptibility and lay the foundation for novel AF therapies.

项目摘要 /摘要该提议的总体目标是探索NFATC1作为新颖的分子和电生理作用心房颤动（AF）敏感性基因，并定义NFATC1对房屋的贡献兴奋性。 AF是临床实践中最常见的持续性心律失常，具有经济负担超过70亿美元的年度医疗保健费用。新兴证据暗示心脏转录因子一般人群中AF和AF的两种家族形式的发病机理。我们确定了一个突变高风险犹他州的犹他州血统AF定义的心脏转录因子NFATC1。 NFATC1是Ca2+ - 依赖转录因子假定在心脏发展中发挥作用，但到目前为止从未有过与心脏兴奋性有关。我们令人兴奋的初步数据确定了NFATC1在调节中的新作用心房兴奋性，该NFATC1无效斑马鱼会发展出自发性心律失常和少年突然死亡。 AIM 1试图定义突变体NFATC1的生化，分子和电生理基础功能障碍，使用HL-1心房细胞系，人类细胞培养模型（患者特异性和基因组编辑诱导多能干细胞得出的心肌细胞，IPSC-CMS）和整个动物模型（转基因斑马鱼）。 AIM 2表征了NFATC1通过探索分子来调节心房兴奋性的作用 NFATC1无效斑马鱼中心律失常的电生理基础。 AIM 3将定义NFATC1- 使用单细胞RNA-受控的转录网络和基因途径调节心脏兴奋性人体中庭和NFATC1 NULL和WT IPSC-CMS中的Seq，Chip-Seq和Chip-Mass光谱。我们的建议利用人类遗传学，基因组编辑技术，最先进的下一代测序全面表征NFATC1的新作用在心脏兴奋性和AF发病机理中。对调节离子的关键转录网络的理解渠道基因表达和心房兴奋性将提供更广泛，更全面的理解心律不齐的敏感性，并为新型AF疗法奠定了基础。