The molecular mechanisms underlying arrhythmogenic right ventricular dysplasia/ca

致心律失常性右心室发育不良/ca的分子机制

• 批准号: 8041043
• 负责人: Farah Sheikh
• 金额: $ 44.34万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8041043
• 关键词: 3-Dimensional; Ablation; Adhesions; Adrenergic Receptor; Affect; Anterior; Anti-Arrhythmia Agents; Arrhythmogenic Right Ventricular Dysplasia; Binding; Biological Models; Bundle-Branch Block; Cardiac; Cardiac Myocytes; Cardiac conduction system; Cardiomyopathies; Cell Adhesion; Cell Adhesion Molecules; Cell-Cell Adhesion; Cells; Cessation of life; Clinical; Connexin 43; Connexins; Defect; Deposition; Desmosomes; Disease; Exhibits; Fibroblasts; Genetic; Goals; Health; Heart; Human; Human Genetics; In Vitro; Intercalated disc; Intercellular Junctions; Intervention; Ion Channel; Laboratories; Lead; Left Ventricular Dysfunction; Left ventricular structure; Link; Modeling; Molecular; Molecular Target; Mus; Muscle Cells; Myocardium; Myosin Light Chains; Nuclear Translocation; Pathway interactions; Pharmaceutical Preparations; Phenotype; Physiological; Play; Population; Potassium Channel; Process; Randomized Controlled Clinical Trials; Right ventricular structure; Role; Signal Transduction; Tachycardia; Testing; Ventricular; Ventricular Arrhythmia; Ventricular Tachycardia; Ventricular septum; desmoplakin; efficacy testing; gene therapy; human disease; improved; in vivo; mouse model; outcome forecast; overexpression; plakoglobin; postnatal; research study; small hairpin RNA; sudden cardiac death; therapeutic target; tool

DESCRIPTION (provided by applicant): Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a genetic form of cardiomyopathy, which is typically characterized by right but also recently left ventricular dysfunction, fibrotic/fatty replacement of the ventricle and ventricular arrhythmias leading to sudden cardiac death. We have generated a mouse model of ARVD/C through conditional cardiac-specific ablation of the desmosomal component, desmoplakin, (desmo cKO) using the myosin-light chain-2v (MLC2v)-Cre mouse. Since MLC2v-Cre is expressed in a range of cardiomyocyte lineages, we propose to identify the subsets of myocyte populations contributing to the distinct phenotypic aspects observed in our model. Our model exhibits unique effects on connexin signaling, which are thought to play a key role in myocyte-myocyte and myocyte-fibroblast adhesion. Thus, we also propose to determine how defects in connexin signaling lead to changes in myocyte-myocyte and myocyte- fibroblast adhesion and contribute to phenotypic aspects of ARVD/C. Our model also exhibits cardiac cytosolic 2-catenin accumulation, which is an effect known to lead to aberrant 2-catenin nuclear translocation/ signaling. Thus, we propose to rescue our ARVD/C model by inhibiting 2-catenin's actions and signaling using a gene therapy approach. We also propose to assess the effects of inhibiting potassium ion channel and 2-adrenergic receptor actions in our ARVD/C model. The goal of this five-year proposal is to understand the cellular mechanisms underlying the various clinical features of ARVD/C as well as test the effects of current and new drug treatments as well as inhibiting 2-catenin's actions on the prognosis of our ARVD/C model. These results have led us to the hypotheses that desmoplakin plays an essential role in subsets of cardiomyocyte lineages and desmoplakin defects cause (i) connexin signaling defects which affect myocyte-myocyte and myocyte- fibroblast adhesion and mislocalization/loss of cell adhesion/junctional components, which affect myocyte cell fate and result in ARVD/C. Specific Aims include: (1) To determine the subset of cardiomyocytes responsible for ARVD/C, by ablating desmoplakin in distinct cardiomyocyte lineages. (2) To determine how connexin signaling affects myocyte-myocyte and myocyte-fibroblast adhesion in our model. (3) To rescue or alter the progression of ARVD/C in our model by inhibiting the actions of (a) 2-catenin's as well as the (b) K+ ion channel and 2-adrenergic receptor. PUBLIC HEALTH RELEVANCE: The goal of this five-year proposal is to (i) understand the cellular mechanisms underlying the various clinical features of the fatal human disease, arrhythmogenic right ventricular dysplasia/ cardiomyopathy (ARVD/C) and (ii) study the impact of manipulating molecular targets and administering current and new drug treatments for ARVD/C on the prognosis of a test mouse model, which we have generated to genetically carry the human disease ARVD/C. These studies will identify molecular pathways that are essential for the progression of ARVD/C and thereby improve our general understanding of this disease, as well as identify therapeutic targets for treating this fatal disease.

描述（由申请人提供）：心律失常性右室发育不良/心肌病（ARVD/C）是一种遗传性心肌病，其典型特征是右心室功能障碍，最近也有左心室功能障碍，心室纤维化/脂肪替代和室性心律失常导致心源性猝死。我们使用肌球蛋白轻链-2v (MLC2v)-Cre小鼠，通过条件性心脏特异性消融桥粒成分桥粒蛋白（desmoplakin, desmocko），建立了ARVD/C小鼠模型。由于MLC2v-Cre在一系列心肌细胞谱系中表达，我们建议确定导致我们模型中观察到的不同表型方面的心肌细胞群亚群。我们的模型显示了连接蛋白信号的独特作用，连接蛋白信号被认为在肌细胞-肌细胞和肌细胞-成纤维细胞粘附中起关键作用。因此，我们还提出确定连接蛋白信号传导缺陷如何导致肌细胞-肌细胞和肌细胞-成纤维细胞粘附的变化，并促进ARVD/C的表型方面。我们的模型还显示了心脏细胞质2-连环蛋白的积累，这是一种已知的导致2-连环蛋白核易位/信号传导异常的效应。因此，我们建议通过基因治疗方法抑制2-catenin的作用和信号传导来挽救我们的ARVD/C模型。我们还建议在ARVD/C模型中评估抑制钾离子通道和2-肾上腺素能受体的作用。这项为期五年的计划的目标是了解ARVD/C各种临床特征的细胞机制，测试当前和新的药物治疗的效果，以及抑制2-catenin对ARVD/C模型预后的作用。这些结果使我们提出了这样的假设，即桥蛋白在心肌细胞谱系的亚群中起着重要作用，桥蛋白缺陷导致(i)连接蛋白信号缺陷，影响肌细胞-肌细胞和肌细胞-成纤维细胞的粘附和细胞粘附/连接成分的错定位/丢失，从而影响肌细胞的命运并导致ARVD/C。具体目的包括：(1)通过在不同的心肌细胞谱系中消融桥蛋白，确定与ARVD/C相关的心肌细胞亚群。(2)在我们的模型中确定连接蛋白信号如何影响肌细胞-肌细胞和肌细胞-成纤维细胞粘附。(3)通过抑制(a) 2-catenin's、(b) K+离子通道和2-肾上腺素能受体的作用来挽救或改变我们模型中ARVD/C的进展。公共卫生相关性：这项为期五年的计划的目标是：(i)了解致命的人类疾病，心律失常性右心室发育不良/心肌病（ARVD/C）的各种临床特征背后的细胞机制，（ii）研究操纵分子靶点和给药ARVD/C的现有和新的药物治疗对测试小鼠模型预后的影响，我们已经产生了遗传携带人类疾病ARVD/C。这些研究将确定对ARVD/C进展至关重要的分子途径，从而提高我们对这种疾病的总体认识，并确定治疗这种致命疾病的治疗靶点。