Role of desmosomes in cardiac electrical function

桥粒在心电功能中的作用

基本信息

批准号：
9332423
负责人：
Mario Delmar
金额：
$ 63.65万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-15 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9332423
关键词：
ANK3 gene Adhesions Adult Anatomy Animal Model Arrhythmia Arrhythmogenic Right Ventricular Dysplasia Calcium Cardiac Cardiac Myocytes Cell Adhesion Molecules Cell-Cell Adhesion Coupling Data Desmosomes Dilatation - action Dilated Cardiomyopathy Dimensions Disease Economics Electrophysiology (science)Event Exons Extracellular Space Failure Functional disorder Funding Genetic Genetic Transcription Goals Heart Heart Arrest Heart failure Homeostasis Human Imagery Incidence Infiltration Inherited Intercalated disc Ion Channel Isoproterenol Knock-out Left Left Ventricular Function Life Link Macromolecular Complexes Mechanics Methods Microscopy Modernization Molecular Morbidity - disease rate Mus Muscle Cells Mutation Myocardium Natural History PRKCA gene Pathway interactions Phase Phenotype Physiology Plus End of the Microtubule Property Proteins Ranvier&apos s Nodes Research Research Personnel Role Secondary to Signal Transduction Site Sodium Structural Protein Structural defect Symptoms Syncope Tamoxifen Techniques Time Tissues Ventricular Ventricular Arrhythmia Ventricular Remodeling Work base beta catenin cost electrical property heart rhythm high risk mortality nano nanoscale novel therapeutics plakophilin 2 programs protein function scaffold sudden cardiac death

项目摘要

PROJECT SUMMARY Our long-term goal is to understand the relation between adhesion molecules and cardiac electrical function. We center on Plakophilin-2 (PKP2), a molecule classically defined as a component of the desmosome, though also known to cover functions beyond cell-cell adhesion. Mutations in PKP2 are recognized as the most common cause of familial arrhythmogenic right ventricular cardiomyopathy (ARVC) of known genetic origin. ARVC is characterized by fibrofatty infiltration, most commonly of right ventricular predominance, ventricular arrhythmias and sudden cardiac death in the young. RV predominance and the high incidence of life- threatening arrhythmias during the early stages of disease have puzzled investigators for years. The study of these features has been hampered by the lack of an animal model that reproduces the natural course of this condition. We have generated a cardiac-specific, tamoxifen-activated, PKP2 knockout murine line (PKP2- cKO). To our knowledge, this is the first animal model with an arrhythmogenic cardiomyopathy of right ventricular predominance that results from PKP2 dysfunction. Our aims are: 1: To characterize the arrhythmogenic phenotype following loss of PKP2 expression. Hypothesis: We propose that loss of PKP2 expression leads to a stage of arrhythmogenicity that precedes heart failure, characterized by asymmetric electrical remodeling of the ventricles. We further propose that such remodeling involves changes in electrical coupling and in sodium current properties, and that arrhythmias are triggered by dysregulation of Cai homeostasis. We postulate that this alteration is, in part, secondary to a) alterations in exon usage and b) changes in transcription of genes not previously linked to adhesion-related pathways and yet relevant to electrophysiology. 2: To characterize the nano-structural phenotype following loss of PKP2 expression. Hypothesis: We postulate that the recently described adhesion/excitability nodes (“mini-nodes of Ranvier”) at the ID act as points of convergence of two signaling platforms: One scaffolded by Ankyrin-G and the other, by PKP2. We further propose that loss of PKP2 expression leads to separation and eventual loss of the components of the adhesion/excitability node, including three key initiators of intracellular signaling cascades: CAMKII, PKCα and beta-catenin. We speculate that these changes are accompanied by asymmetrical (right vs left) changes in a) intercellular space dimensions and b) the anatomy of the dyad, thus contributing to the functional changes observed in the early-stage arrhythmogenic phenotype.

项目概要我们的长期目标是了解粘附分子与心电功能之间的关系。我们以 Plakophilin-2 (PKP2) 为中心，这是一种经典定义为桥粒组成部分的分子，但还已知 PKP2 的突变涵盖细胞与细胞粘附以外的功能。已知遗传起源的家族性心律失常性右心室心肌病 (ARVC) 的常见原因。 ARVC 的特点是纤维脂肪浸润，最常见的是右心室为主，心室心律失常和心源性猝死在年轻人中占主导地位并且死亡率很高。疾病早期阶段的威胁性心律失常多年来一直困扰着研究人员。由于缺乏重现这种自然过程的动物模型，这些功能受到了阻碍我们已经生成了心脏特异性、他莫昔芬激活的 PKP2 敲除小鼠系（PKP2-）。据我们所知，这是第一个患有右心律失常性心肌病的动物模型。 PKP2 功能障碍导致的心室优势我们的目标是： 1：描述 PKP2 功能障碍的特征。 PKP2 表达缺失后的致心律失常表型假设：我们提出 PKP2 表达缺失。表达导致心力衰竭之前的心律失常阶段，其特征是不对称我们进一步提出，这种重塑涉及电的变化。耦合和钠电流特性，并且心律失常是由蔡失调引发的我们假设这种改变部分是继发于 a) 外显子使用的改变和 b) 以前与粘附相关途径无关但与粘附相关的基因转录的变化电生理学2：表征PKP2表达缺失后的纳米结构表型。假设：我们假设最近描述的粘附/兴奋性节点（“Ranvier 迷你节点”）位于 ID 作为两个信号平台的汇聚点：一个由 Ankyrin-G 搭建，另一个由 Ankyrin-G 搭建。我们进一步提出 PKP2 表达的丧失会导致分离并最终丧失。粘附/兴奋性节点的组成部分，包括细胞内信号级联的三个关键启动子：我们推测这些变化伴随着 CAMKII、PKCα 和 β-catenin 的不对称（右 vs）。左）a）细胞间隙尺寸和 b）二元体解剖结构的变化，从而导致在早期致心律失常表型中观察到的功能变化。