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：
10449135
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/10449135
关键词：
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 Cardiac development 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 Play Predisposition Property Recovery Refractory Reporter Risk Role Siblings Signal Pathway Sinus Site Sudden Death Susceptibility Gene Tachyarrhythmias Techniques Testing Transcriptional Activation Transgenic Organisms Utah Variant Zebrafish base bioinformatics tool 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 induced pluripotent stem cell derived cardiomyocytes innovation insight mutant mutation carrier next generation sequencing novel overexpression rare variant response risk stratification 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.

项目概要/摘要该提案的总体目标是探索 NFATC1 作为一种新型药物的分子和电生理作用。心房颤动 (AF) 易感基因，并定义 NFATC1 对心房颤动的先前未知的贡献兴奋性。房颤是临床实践中最常见的持续性心律失常，具有经济负担每年的医疗保健费用超过 70 亿美元。新的证据表明心脏转录因子 AF 家族型和一般人群中 AF 的发病机制。我们发现了一个突变心脏转录因子 NFATC1 在由年轻发病 AF 定义的高危犹他州家系中。 NFATC1 是一种 Ca2+- 依赖转录因子被认为在心脏发育中发挥作用，但迄今为止从未被证实与心脏兴奋性有关。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，nfatc1 缺失的斑马鱼会出现自发性房性快速心律失常和幼年突发性猝死死亡。目标 1 试图确定 NFATC1 突变体的生化、分子和电生理学基础功能障碍，使用 HL-1 心房细胞系，一种人类细胞培养模型（患者特异性和基因组编辑诱导多能干细胞衍生的心肌细胞（iPSC-CM）和整个动物模型（转基因斑马鱼）。目标 2 通过探索分子机制来表征 NFATC1 在调节心房兴奋性中的作用 nfatc1 缺失斑马鱼房性快速心律失常的电生理学基础。目标 3 将定义 NFATC1- 使用单细胞 RNA-控制转录网络和调节心脏兴奋性的基因途径人心房以及 NFATC1 null 和 WT iPSC-CM 中的 Seq、ChIP-Seq 和 ChIP-质谱。我们的提案利用了人类遗传学、基因组编辑技术、最先进的下一代测序模态和生物信息学以及电生理学来全面表征 NFATC1 的新作用心脏兴奋性和 AF 发病机制。了解调节离子的关键转录网络通道基因表达和心房兴奋性将提供更广泛、更全面的理解心律失常易感性的研究，为新型 AF 疗法奠定基础。