Role of PKP2 in epicardial structure and function

PKP2 在心外膜结构和功能中的作用

基本信息

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
项目类别：
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

项目摘要

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.

项目概要 Plakophilin-2 (PKP2) 是桥粒的一个组成部分，最近的研究表明 PKP2 也是桥粒的一个组成部分。充当细胞内信号复合物的支架，并作为微管锚定平台的一部分 PKP2 的突变与约 50% 的致心律失常病例有关。已知遗传起源的室性心肌病（ARVC）是一种遗传性疾病，其特征是。心室质量被纤维和脂肪组织替代，心室的易感性增加我们的长期目标是：1）确定年轻人的心律失常和猝死。成纤维细胞和脂肪细胞填充在受 ARVC 影响的心脏的心室壁中，2) 定义了作用于祖细胞群以产生疾病表型的分子机制。重点关注心外膜细胞，这是一种驻留在心脏的多能干细胞群，可产生各种非我们的中心假设是，在原位心外膜细胞中，PKP2。缺乏会破坏细胞间连接及其相关的细胞内信号节点的结构；破坏会改变细胞功能并导致促纤维化、促心律失常表型。是：1）定义细胞间连接的分子解剖学，以及细胞间连接的结构/功能心外膜细胞中相应的细胞内信号平台。 PKP2 是心外膜细胞的功能组成部分：a) 细胞间连接，b) 锚定平台微管正端，以及 c) 细胞内信号中枢的支架，其中包括 β-连环蛋白，我们进一步提出，在心外膜细胞中，PKP2 表达的丧失会导致分离和分离。细胞间连接和信号传导节点的成分丢失，从而驱动——除其他事件外—— Rho 依赖性 MRTF 活性，随后激活运动基因程序，促进纤维化表型 2) 描述 PKP2 缺乏对心外膜细胞功能的影响，及其对心脏解剖学和电生理学的影响假设：我们提出 PKP2 缺失。在体内的心外膜细胞中驱动心外膜来源的祖细胞及其它们的过度动员随后在发育过程中和对心脏损伤的反应中分化为纤维脂肪组织。进一步提出，损伤后心外膜来源的成纤维细胞群的扩张会产生电脉冲传播的不均匀分布的解剖学障碍，并且这些障碍物的尺寸因 PKP2 表达而异。