Altered Cell-Cell Coupling in Arrhythmogenic Cardiomyopathy

致心律失常性心肌病中细胞间偶联的改变

• 批准号: 10202697
• 负责人: JEFFREY E SAFFITZ
• 金额: $ 43.75万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10202697
• 关键词: Acute; Adult; Anatomy; Arrhythmia; Biology; Cardiac development; Cells; Chronic; Cicatrix; Clinical; Collaborations; Complex; Connexin 43; Connexins; Coupling; Data; Defect; Development; Dilated Cardiomyopathy; Disease; Disease Pathway; Excision; Fibrosis; Functional disorder; Gap Junctions; Goals; Heart; Heart Diseases; Heart Injuries; Heart failure; Hormonal; Human; Hypertrophic Cardiomyopathy; Hypertrophy; Incidence; Individual; Injury; Intercalated disc; Link; Measurement; Measures; Mediating; Methods; Modeling; Molecular; Mus; Muscle Cells; Mutation; Myocardial Ischemia; Paper; Pathologic; Patients; Pattern; Phase; Phenotype; Phosphorylation; Plant Roots; Property; Proteins; Research; Research Personnel; Resolution; Robin bird; Role; Signal Transduction; Structure; Sudden Death; Testing; Tissues; Ventricular; arrhythmogenic cardiomyopathy; authority; base; computerized tools; density; design; disease phenotype; gap junction channel; indium arsenide; ischemic cardiomyopathy; novel; prevent; small molecule; success; sudden cardiac death; tissue preparation; trafficking; virtual

Project Summary/Abstract The goal of this project is to elucidate mechanisms responsible for gap junction remodeling in arrhythmogenic cardiomyopathy (ACM), a leading cause of sudden death in the young and especially in athletes. Gap junction remodeling occurs early in ACM, well before development of fibro-fatty scar tissue and contractile dysfunction. Arrhythmias occur frequently during this so-called “concealed phase” and appear to arise through interactions between altered cell-cell electrical coupling and reduced INa and IK1. Here, we propose studies to define, at a level of detail never before achieved, how gap junction remodeling occurs in this highly arrhythmogenic human heart disease and how it promotes sudden death. Moreover, we have a small molecule that reverses gap junction remodeling in ACM. Thus, we will not only define the mechanism of gap junction remodeling in ACM, but will also define the mode of action of a mechanism-based therapy that may eventually be used in patients. In the proposed research, we will use state-of-the-art methods to rigorously quantify changes in Cx43 expression at intercalated discs and measure cell-cell conductance in ventricular myocytes expressing ACM- causing desmosomal mutations (such measurements. We will characterize changes in impulse propagation at a subcellular level of resolution in precisely patterned tissue preparations and in intact adult mouse hearts using multiple models that faithfully recapitulate the ACM disease phenotype seen in patients. We will use powerful computational tools to define interactions between reduced cell-cell electrical coupling and reduced INa and IK1current densities, and precisely determine their individual contributions to conduction abnormalities and arrhythmogenesis. We will perform detailed studies in collaboration with Robin Shaw, a leading authority in connexin trafficking, to define molecular mechanisms responsible for gap junction remodeling in ACM. We will define the role of EB1-based forward Cx43 trafficking in ACM, and investigate the role of changes in Cx43 phosphorylation and internalization. We will also elucidate molecular mechanisms by which abnormal translocation of the GSK3β/APC/Axin complex to the intercalated disc interferes with Cx43 trafficking in ACM. The ultimate objective is to develop new ways to prevent sudden death in ACM by correcting the trafficking defect that appears to be at the root of lethal rhythm disorders in this disease spectrum.

项目摘要/摘要 该项目的目的是阐明导致心律不齐中间隙连接重塑的机制 心肌病（ACM），这是年轻人，尤其是运动员突然死亡的主要原因。间隙交界处 重塑发生在ACM的早期，良好，在纤维脂肪疤痕组织和收缩功能障碍的发展之前。 心律不齐是在所谓的“隐藏阶段”中经常发生的，并且似乎是通过相互作用而产生的 在细胞电池电耦合和减少INA和IK1之间。在这里，我们建议在一个研究中定义研究 从未达到的细节水平，间隙连接重塑如何发生在这种高度心律失常的人体中 心脏病及其如何促进猝死。此外，我们有一个小分子可以逆转差距 ACM中的连接重塑。这是，我们不仅将定义ACM中间隙连接重塑的机制， 但还将定义基于机制的治疗的作用方式，该治疗有时可能在患者中使用。 在拟议的研究中，我们将使用最先进的方法来严格量化CX43的变化 插入式椎间盘的表达并测量表达ACM-的心室肌细胞中的细胞细胞电导 引起脱骨突变（此类测量。我们将表征脉冲传播的变化 精确图案的组织制剂和完整成年小鼠心脏中分辨率的亚细胞分辨率水平 使用多种模型，这些模型忠实地概括了患者中看到的ACM疾病表型。我们将使用 强大的计算工具来定义减少的细胞电池电气耦合和减少之间的相互作用 ina和ik1电流密度，并精确地确定其个人对异常的贡献 和心律失常。我们将与领先当局Robin Shaw合作进行详细的研究 在连接蛋白运输中，定义了负责ACM中间隙连接重塑的分子机制。我们 将定义基于EB1的远期CX43运输在ACM中的作用，并研究CX43变化的作用 磷酸化和内在化。我们还将阐明异常的分子机制 GSK3β/APC/AXIN复合物转移到ACM中CX43运输的插入式椎间盘干扰上。 最终目标是开发新的方法来通过纠正贩运来防止ACM突然死亡 在这种疾病谱系中似乎是致命性节奏疾病的根源的缺陷。

项目成果

Edward E. Carmeliet, MD, PhD (January 4, 1930-April 5, 2021): A pioneer in cardiac cellular electrophysiology.

Edward E. Carmeliet，医学博士、哲学博士（1930年1月4日至2021年4月5日）：心脏细胞电生理学的先驱。

• 发表时间: 2021
• 期刊: Heart rhythm
• 影响因子: 5.5
• 作者: Kléber,AndréG;Rosen,MichaelR;Janse,MichielJ;Noble,Denis
• 通讯作者: Noble,Denis

Determinants of electrical propagation and propagation block in Arrhythmogenic Cardiomyopathy.

致心律失常性心肌病中电传播和传播阻滞的决定因素。

• DOI: 10.1016/j.yjmcc.2023.11.003
• 发表时间: 2024
• 期刊: Journal of molecular and cellular cardiology
• 影响因子: 5
• 作者: Jin,Qianru;Lee,KeelYong;Selimi,Zoja;Shimura,Daisuke;Wang,Ethan;Zimmerman,JohnF;Shaw,RobinM;Kucera,JanP;Parker,KevinKit;Saffitz,JeffreyE;Kleber,AndreG
• 通讯作者: Kleber,AndreG