The role N-terminal acetylation in dilated cardiomyopathy and associated arrhythmia

N-末端乙酰化在扩张型心肌病和相关心律失常中的作用

基本信息

批准号：
10733915
负责人：
Vassilios James Bezzerides
金额：
$ 68万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-03 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10733915
关键词：
Ablation Acetylation Acetyltransferase Action Potentials Affect Animal Model Arrhythmia Biological Models Calcium Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular Diseases Catalytic Domain Characteristics Complex Data Developmental Delay Disorders Dilated Cardiomyopathy Disease Electrophysiology (science)Family Family member Female Fibrosis Functional disorder Genetic Predisposition to Disease Heart Heart Abnormalities Heart Diseases Heart failure Homeostasis Human Impairment Individual Ion Channel Ions Knockout Mice Learning Disabilities Mediating Modeling Modification Morbidity - disease rate Mutation Myocardial Myocardial dysfunction N-terminal Patients Phenotype Physiological Post-Translational Protein Processing Potassium Potassium Channel Proteins Proteome Proteomics Recurrence Risk Role Sodium Sodium Channel Structure Sudden Death Testing Ventricular Arrhythmia Ventricular Dysfunction autism spectrum disorder boys clinical phenotype congenital heart disorder genetic pedigree heart function heart rhythm improved induced pluripotent stem cell induced pluripotent stem cell derived cardiomyocytes insight kindred male mortality mouse model novel overexpression pressure protein complex risk stratification stem cell model therapeutic development

项目摘要

PROJECT SUMMARY Cardiomyopathy and heart failure are leading causes of morbidity and mortality world-wide. In addition to ventricular dysfunction, heart-failure associated ventricular arrhythmias cause sudden death with few disease-modifying therapies. Changes in myocardial conduction, increased fibrosis, alterations of ion channel characteristics and genetic susceptibilities have all been postulated to underlie the increased risk of arrhythmia in heart failure, but no unifying mechanism is known. Post- translational modifications (PTMs) of cardiac proteins have emerged as critical factors in mediating normal physiologic function or leading to heart disease when dysregulated. Recently mutations in the N-terminal acetyltransferase complex type A (NatA) have been identified in patients with congenital heart disease, cardiomyopathy, and arrhythmia. This protein complex acetylates the N-terminus of nascent proteins regulating stability, subcellular localization, and complex formation, with nearly 40% of the proteome as potential targets. We have recently identified a large family with a novel mutation in the catalytic subunit of NatA, NAA10. Male patients have severely prolonged QTs, recurrent arrhythmias, developmental delay, learning disabilities, and cardiomyopathy, with female patients more variably affected. We created models of NAA10 dysfunction using induced pluripotent stem cells (iPSCs) derived from several affected male patients. Electrophysiologic analysis of differentiated iPSC-derived cardiomyocytes (iPSC-CMs) demonstrated action potential duration (APD) prolongation, abnormalities of sarcomeric structure, calcium handling and corresponding dysregulation of sodium and potassium currents. Establishing a network of collaborators, we investigated the mechanism of NAA10 dysfunction and developed an animal model for cardiac- specific ablation of NAA10. We propose to use our scalable model systems to investigate the currently unknown role of N-terminal acetylation within the heart as an entry point to understanding the mechanisms of arrhythmia risk in heart failure. In Aim 1, we will determine the mechanism of how N-terminal acetylation regulates sodium and potassium ion channels along with the discovery of other target proteins. In Aim 2, we will use recently developed murine models to selectively ablate Naa10 and the paralogue Naa12 within the heart to determine the causative mechanisms of N-terminal acetylation in heart failure and arrhythmogenesis. In Aim 3, we examine the contribution of N-terminal acetylation in acquired forms of heart disease including human heart failure. This transformative proposal will provide novel mechanistic insight into the poorly understood role of N-terminal acetylation in cardiovascular disease with potential for improved arrhythmia risk stratification and therapeutic development.

项目概要心肌病和心力衰竭是全世界发病和死亡的主要原因。在除了心室功能障碍外，心力衰竭相关的室性心律失常还会导致突发性心律失常。很少有疾病缓解疗法导致死亡。心肌传导的变化，纤维化增加，离子通道特征和遗传易感性的改变都被假设为是心力衰竭心律失常风险增加的基础，但尚无统一机制。邮政- 心脏蛋白的翻译修饰（PTM）已成为介导的关键因素正常的生理功能或失调时导致心脏病。最近突变已在先天性痴呆患者中发现了 A 型 N 末端乙酰转移酶复合物 (NatA) 心脏病、心肌病和心律失常。该蛋白质复合物乙酰化 N 末端新生蛋白调节稳定性、亚细胞定位和复合物形成，近 40% 蛋白质组作为潜在目标。我们最近发现了一个具有新突变的大家族位于 NatA 的催化亚基 NAA10 中。男性患者QT间期严重延长，且反复发作女性患者出现心律失常、发育迟缓、学习障碍和心肌病受到的影响更加不同。我们使用诱导多能干细胞创建了 NAA10 功能障碍模型来自几名受影响的男性患者的细胞（iPSC）。分化的电生理分析 iPSC 衍生的心肌细胞 (iPSC-CM) 表现出动作电位持续时间 (APD) 延长、肌节结构异常、钙处理和相应的钠和钾电流失调。建立合作者网络，我们研究了 NAA10 功能障碍的机制并开发了心脏疾病动物模型 NAA10 的特异性消融。我们建议使用我们的可扩展模型系统来研究目前未知的 N 末端乙酰化在心脏中的作用作为理解的切入点心力衰竭心律失常风险的机制。在目标 1 中，我们将确定如何实现的机制 N 末端乙酰化调节钠离子通道和钾离子通道以及其他通道的发现目标蛋白质。在目标 2 中，我们将使用最近开发的小鼠模型来选择性消融 Naa10 和心脏内的旁系同源物 Naa12 以确定 N 末端的致病机制心力衰竭和心律失常发生中的乙酰化。在目标 3 中，我们检查 N 端的贡献获得性心脏病（包括人类心力衰竭）中的乙酰化。这种变革性的该提案将为人们对 N 末端的作用知之甚少提供新颖的机制见解心血管疾病中的乙酰化有可能改善心律失常风险分层和治疗的发展。