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 本项目的目标是阐明致心律失常中缝隙连接重构的机制。 心肌病(ACM)，年轻人，尤其是运动员猝死的主要原因。缝隙结 重构发生在ACM的早期，远在纤维脂肪瘢痕组织和收缩功能障碍发展之前。 心律失常在这一所谓的“隐匿期”中经常发生，似乎是通过相互作用而出现的。 细胞-细胞电耦合改变和INA和Ik1减少之间的关系。在这里，我们建议进行研究，以定义 前所未有的细节水平，缝隙连接重塑是如何在这个高度心律失常的人身上发生的 心脏病以及它如何导致猝死。此外，我们有一种小分子可以逆转缺口 ACM的交界处重塑。因此，我们不仅将明确ACM缝隙连接重塑的机制， 但也将定义一种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严格量化Cx43的变化 ACM-1在细胞间盘的表达及细胞间电导的测定 导致桥粒突变(这样的测量。我们将在以下位置描述脉冲传播的变化 精确构图的组织制剂和完整的成年小鼠心脏的亚细胞水平的分辨率 使用多种模型，真实地概括了患者中所见的ACM疾病表型。我们将使用 强大的计算工具，用于定义减少的电池-电池电耦合和减少的电池之间的相互作用 INA和Ik1的电流密度，并精确地确定它们对传导异常的单独贡献 以及心律失常的发生。我们将与领先的权威罗宾·肖合作进行详细的研究 在缝隙连接蛋白运输中，确定负责ACM缝隙连接重塑的分子机制。我们 将定义基于EB1的转发Cx43在ACM中的作用，并调查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 β/APC/Axin复合体移位到间盘干扰Cx43在ACM中的运输。 最终目标是开发新的方法，通过纠正人口贩运来防止ACM的猝死 这种缺陷似乎是这种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