Role of desmosomes in cardiac electrical function

桥粒在心电功能中的作用

• 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
• 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' 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

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.

项目摘要 我们的长期目标是了解粘附分子和心脏电功能之间的关系。 我们集中在Plakophilin-2（PKP2），一种经典定义为桥粒组分的分子， 也已知其涵盖细胞-细胞粘附以外的功能。PKP2的突变被认为是 已知遗传来源的家族性致瘤性右心室心肌病（ARVC）的常见原因。 ARVC的特征是纤维脂肪浸润，最常见的是右心室优势，心室 年轻人的心律失常和心源性猝死。RV占优势和生命的高发病率- 在疾病的早期阶段，危险的心律失常困扰了研究人员多年。研究 这些特征由于缺乏动物模型来再现这种自然过程而受到阻碍。 条件我们已经产生了心脏特异性的、他莫昔芬激活的、PKP2敲除的鼠系（PKP2-PKP3）。 cKO）。据我们所知，这是第一个右室心肌病的动物模型。 PKP2功能障碍导致的心室优势。我们的目标是：1： PKP2表达丧失后的致心律失常表型。假设：我们认为PKP2的缺失 表达导致心力衰竭之前的促血小板生成性阶段，其特征在于不对称性血小板聚集。 心室的电重构我们进一步提出，这种重塑涉及到电生理的变化， 偶联和钠电流特性，心律失常是由Cai的失调触发的。 体内平衡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） 先前与粘附相关通路无关但与 电生理学2：表征PKP2表达丧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（"兰维尔小节点"）， ID充当两个信令平台的汇聚点：一个由Anklove-G搭建，另一个由 PKP2.我们进一步提出，PKP2表达的缺失导致了细胞的分离和最终的丧失。 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： CAMKII、PKC α和β-连环蛋白。我们推测，这些变化伴随着不对称（右vs 左）a）细胞间隙尺寸和B）二分体解剖结构的变化，从而有助于 在早期致突变表型中观察到的功能变化。