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

• 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
• 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

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.

项目摘要 心肌病和心力衰竭是世界范围内发病率和死亡率的主要原因。在 除了心室功能障碍之外，心力衰竭相关的室性心律失常引起突发性心律失常， 几乎没有改善疾病的治疗方法。心肌传导改变，纤维化增加， 离子通道特性和遗传亲合性的改变都被假定为 是心力衰竭时心律失常风险增加的基础，但尚无统一的机制。后 心脏蛋白质的翻译修饰（PTM）已经成为介导心肌细胞凋亡的关键因素。 正常生理功能或在失调时导致心脏病。最近， N-末端乙酰转移酶复合物A型（NatA）已在先天性 心脏病、心肌病和心律失常。这种蛋白质复合物乙酰化的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% 蛋白质组作为潜在的目标。我们最近发现了一个带有新突变的大家族 在NatA的催化亚基NAA 10中。男性患者QT间期严重延长，复发 心律失常、发育迟缓、学习障碍和心肌病，女性患者 更受影响。我们使用诱导的多能干细胞建立了NAA 10功能障碍模型， 细胞（iPSC）来自几个受影响的男性患者。分化型心肌梗死的电生理分析 iPSC衍生的心肌细胞（iPSC-CM）表现出动作电位时程（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NAA 10功能障碍的机制，并建立了一种心血管疾病的动物模型。 特异性消融NAA 10。我们建议使用我们的可扩展模型系统来研究 目前尚不清楚N-末端乙酰化在心脏中的作用， 心力衰竭中心律失常风险的机制。在目标1中，我们将确定 N-末端乙酰化调节钠和钾离子通道沿着的发现， 靶蛋白。在目标2中，我们将使用最近开发的小鼠模型来选择性地消融Naa 10 和心脏内的para-Naa 12，以确定N-末端的致病机制。 乙酰化在心力衰竭和心肌梗死中的作用。在目标3中，我们研究了N-末端的贡献， 乙酰化在获得性心脏病包括人心力衰竭中的作用。这种变革性 该提案将提供新的机制深入了解N-末端的作用， 乙酰化在心血管疾病中具有改善心律失常风险分层的潜力， 治疗发展