Role of PKP2 in epicardial structure and function

PKP2 在心外膜结构和功能中的作用

• 批准号: 9262386
• 负责人: Mario Delmar
• 金额: $ 78.91万
• 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: 2016-12-15 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9262386
• 关键词: Ablation; Adhesions; Adipocytes; Adipose tissue; Adult; Affect; Anatomy; Area; Arrhythmia; Arrhythmogenic Right Ventricular Dysplasia; Automobile Driving; Cardiac; Cell physiology; Cells; Collagen; Complex; Data; Deposition; Desmosomes; Detection; Development; Dimensions; Disease; Economics; Electron Microscopy; Electrophysiology (science); Epicardium; Epithelial Cells; Event; Exhibits; Extracellular Matrix; Failure; Fibroblasts; Gap Junctions; Genes; Genetic; Goals; Grant; Heart; In Situ; Inherited; Injury; Intercellular Junctions; Knowledge; Mesenchymal; Methods; Microscopy; Microtubules; Modernization; Molecular; Morbidity - disease rate; Multipotent Stem Cells; Mus; Mutation; PRKCA gene; Patients; Phenotype; Physiology; Play; Pluripotent Stem Cells; Plus End of the Microtubule; Population; Predisposition; Prevention; Proteins; Publishing; Role; Signal Transduction; Site; Small Interfering RNA; Smooth Muscle Actin Staining Method; Source; Stem cells; Structure; Sudden Death; Translating; Ventricular; Ventricular Arrhythmia; base; beta catenin; cardiogenesis; cell motility; cost; disease phenotype; fetal; in vivo; microscopic imaging; migration; mortality; myocardin; novel therapeutics; plakophilin 2; programs; response; rho; scaffold; transcription factor

PROJECT SUMMARY Plakophilin-2 (PKP2) is a component of the desmosome. Recent studies have demonstrated that PKP2 also acts as a scaffold for an intracellular signaling complex, and as part of the microtubule anchoring platform at the site of cell contact. Mutations in PKP2 associate with about 50% of cases of arrhythmogenic right ventricular cardiomyopathy (ARVC) of known genetic origin. ARVC is an inherited disease characterized by replacement of ventricular mass with fibrous and fatty tissue, and an increased susceptibility to ventricular arrhythmias and sudden death in the young. Our long-term goals are to: 1) establish the cellular origin of the fibroblasts and adipocytes that populate the ventricular wall in an ARVC-affected heart, and 2) define the molecular mechanisms that act on the progenitor cell population to bring about the disease phenotype. We focus on epicardial cells, a cardiac-resident pluripotent stem cell population that gives rise to various non- myocyte cardiac cells, including fibroblasts. Our central hypothesis is that, in epicardial cells in situ, PKP2 deficiency disrupts the structure of intercellular junctions and their associated intracellular signaling nodes; this disruption alters cellular function and leads to a pro-fibrotic, pro-arrhythmogenic phenotype. Our Specific Aims are: 1) To define the molecular anatomy of intercellular junctions, and the structure/function of the corresponding intracellular signaling platforms in epicardial cells. Hypothesis: We postulate that in epicardial cells, PKP2 is a functional component of: a) the intercellular junctions, b) the anchoring platform for the microtubule plus-end, and c) the scaffolding of an intracellular signaling hub that includes beta-catenin, PKCα, and RhoA. We further propose that in epicardial cells, loss of PKP2 expression leads to separation and loss of components of both the intercellular junction and the signaling node, thus driving –among other events- Rho-dependent MRTF activity, with the consequent activation of the motile gene program that facilitates the fibrotic phenotype. 2) To characterize the consequences of PKP2 deficiency on epicardial cell function, and their impact on cardiac anatomy and electrophysiology. Hypothesis: We propose that PKP2 deletion in epicardial cells in vivo drives excessive mobilization of epicardium-derived progenitor cells and their subsequent differentiation into fibro-fatty tissue both during development and in response to cardiac injury. We further propose that expansion of the epicardium-derived fibroblast population upon injury creates heterogeneously-distributed anatomic obstacles for propagation of the electrical impulse, and that these obstacles differ in dimensions depending on PKP2 expression.

项目摘要 plakophilin-2（PKP2）是朝向体的组成部分。最近的研究表明，PKP2也 充当细胞内信号复合物的支架，作为微管锚定平台的一部分 细胞接触部位。 PKP2中的突变与大约50％的心律失常右病例相关 已知遗传起源的心室心肌病（ARVC）。 ARVC是一种遗传性疾病，其特征是 用纤维和脂肪组织代替心室肿块，并增加对心室的敏感性 年轻人心律不齐和猝死。我们的长期目标是：1）确定 成纤维细胞和脂肪细胞在受ARVC感染心脏中填充心室壁的成纤维细胞，2）定义 作用于祖细胞群的分子机制，以引起疾病表型。我们 专注于心外膜细胞，心外膜细胞是一种心脏居民多能干细胞群，引起各种非 - 心肌细胞，包括成纤维细胞。我们的中心假设是，在心外膜细胞原位，PKP2 缺陷破坏了细胞间连接的结构及其相关的细胞内信号传导节点；这 破坏会改变细胞功能，并导致促纤维性的，促性心律失常的表型。我们的具体目标 为：1）定义细胞间连接的分子解剖学，以及 心外膜细胞中的相应细胞内信号传导平台。假设：我们假设 心外膜细胞，PKP2是：a）细胞间结的功能组成部分，b） 微管加端，c）包括β-catenin，包括β-catenin的细胞内信号轮毂的脚手架 PKCα和Rhoa。我们进一步建议，在心外膜细胞中，PKP2表达的丧失导致分离和 细胞间连接和信号节点的组件损失，从而驱动其他事件 - RHO依赖性MRTF活性，随之而来的是母子基因程序的激活，促进了 纤维化表型。 2）表征PKP2缺乏对心外膜细胞功能的后果， 它们对心脏解剖学和电生理学的影响。假设：我们建议PKP2删除 在心外膜细胞中，体内驱动心外膜衍生的祖细胞及其其过度动员 随后在发育过程和对心脏损伤的反应过程中分化为纤维脂肪组织。我们 进一步提出的，损伤会增加心外膜衍生的成纤维细胞种群的扩张 异构分布的解剖障碍，用于传播电脉冲，并且这些障碍 根据PKP2表达，障碍的维度有所不同。