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）：致心律失常性右心室发育不良/心肌病（ARVD/C）是心肌病的一种遗传形式，其典型特征是右心室功能障碍，最近也出现左心室功能障碍、心室纤维化/脂肪替代和导致心源性猝死的室性心律失常。我们通过使用肌球蛋白轻链 2v (MLC2v)-Cre 小鼠对桥粒成分桥粒斑蛋白 (desmo cKO) 进行条件性心脏特异性消融，生成了 ARVD/C 小鼠模型。由于 MLC2v-Cre 在一系列心肌细胞谱系中表达，因此我们建议鉴定有助于我们模型中观察到的不同表型方面的心肌细胞群亚群。我们的模型对连接蛋白信号传导表现出独特的作用，连接蛋白信号传导被认为在肌细胞-肌细胞和肌细胞-成纤维细胞粘附中发挥关键作用。因此，我们还建议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以及如何影响 ARVD/C 的表型方面。我们的模型还表现出心脏胞质 2- 连环蛋白积聚，这是一种已知会导致异常 2-连环蛋白核易位/信号转导的效应。因此，我们建议通过使用基因治疗方法抑制 2-连环蛋白的作用和信号传导来拯救我们的 ARVD/C 模型。我们还建议在我们的 ARVD/C 模型中评估抑制钾离子通道和 2-肾上腺素能受体作用的效果。这项为期五年的提案的目标是了解 ARVD/C 各种临床特征背后的细胞机制，测试当前和新药物治疗的效果以及抑制 2-连环蛋白对 ARVD/C 模型预后的作用。这些结果使我们得出这样的假设：桥粒斑蛋白在心肌细胞谱系亚群中发挥重要作用，桥粒斑蛋白缺陷导致（i）连接蛋白信号传导缺陷，影响肌细胞-肌细胞和肌细胞-成纤维细胞粘附以及细胞粘附/连接成分的错误定位/丢失，从而影响肌细胞命运并导致 抗逆转录病毒病/C。具体目标包括： (1) 通过消除不同心肌细胞谱系中的桥粒斑蛋白来确定导致 ARVD/C 的心肌细胞亚群。 (2) 确定连接蛋白信号传导如何影响我们模型中的肌细胞-肌细胞和肌细胞-成纤维细胞粘附。 (3) 通过抑制 (a) 2-连环蛋白以及 (b) K+ 离子通道和 2-肾上腺素受体的作用来挽救或改变我们模型中 ARVD/C 的进展。公共健康相关性：这项五年提案的目标是（i）了解致命性人类疾病、致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，以及（ii）研究操纵分子靶标和施用当前和新的 ARVD/C 药物治疗对我们建立的测试小鼠模型预后的影响 携带人类疾病 ARVD/C 的基因。这些研究将确定 ARVD/C 进展所必需的分子途径，从而提高我们对这种疾病的总体了解，并确定治疗这种致命疾病的治疗靶点。