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.

项目概要/摘要 该项目的目标是阐明致心律失常中缝隙连接重塑的机制 心肌病（ACM）是年轻人、尤其是运动员猝死的主要原因。间隙连接 重塑发生在 ACM 的早期，远早于纤维脂肪疤痕组织和收缩功能障碍的发展。 心律失常经常发生在这个所谓的“隐藏阶段”，并且似乎是通过相互作用引起的 改变的细胞间电耦合与减少的 INa 和 IK1 之间的关系。在这里，我们提出研究来定义， 前所未有的细节水平，间隙连接重塑是如何在高度心律失常的人类身上发生的 心脏病及其如何促进猝死。此外，我们有一种小分子可以逆转间隙 ACM 中的连接重塑。因此，我们不仅定义了 ACM 中间隙连接重塑的机制， 但还将定义最终可能用于患者的基于机制的疗法的作用模式。 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 闰盘表达并测量表达 ACM- 的心室肌细胞的细胞-细胞电导 引起桥粒突变（此类测量。我们将描述脉冲传播的变化 在精确图案化的组织制剂和完整的成年小鼠心脏中实现亚细胞水平的分辨率 使用多种模型忠实地再现患者中所见的 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间电耦合和减少的细胞之间的相互作用 INa 和 IK1 电流密度，并精确确定它们各自对传导异常的贡献 和心律失常发生。我们将与领先权威 Robin Shaw 合作进行详细研究 在连接蛋白运输中，定义负责 ACM 间隙连接重塑的分子机制。我们 将定义基于 EB1 的正向 Cx43 贩运在 ACM 中的作用，并研究 Cx43 变化的作用 磷酸化和内化。我们还将阐明异常的分子机制 GSK3β/APC/Axin 复合物易位至闰盘会干扰 ACM 中的 Cx43 运输。 最终目标是通过纠正贩运来开发新方法来预防 ACM 猝死 缺陷似乎是该疾病谱中致命性节律紊乱的根源。

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