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

基本信息

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
项目类别：
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

项目摘要

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）：心律不齐的右心室发育不良/心肌病（ARVD/C）是心肌病的遗传形式，通常以右但最近的左心室功能障碍，近期左心室功能障碍，纤维化/脂肪替代，曲折/脂肪替代，导致心脏突然心脏突然心脏死亡。我们通过使用肌球蛋白 - 光链-2V（MLC2V）-CRE小鼠的脱发组分（Desmo CKO）的条件性心脏特异性消融生成了ARVD/C的小鼠模型。由于MLC2V-CRE在一系列心肌细胞谱系中表达，因此我们建议识别肌细胞群体的亚群，这些亚群有助于我们在模型中观察到的不同表型方面。我们的模型对连接蛋白信号传导具有独特的作用，该信号被认为在心肌细胞肌细胞和心肌细胞粘附粘附中起关键作用。因此，我们还建议确定连接蛋白信号传导中的缺陷如何导致心肌细胞肌细胞和心肌细胞 - 成纤维细胞粘附的变化，并有助于ARVD/C的表型方面。我们的模型还表现出心脏胞质2-catenin的积累，这是一种已知导致2-catenin核易位/信号传导的作用。因此，我们建议通过使用基因治疗方法抑制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影响。该五年建议的目的是了解ARVD/C各种临床特征的基础机制，并测试当前和新药物处理的影响，并抑制2-Catenin对我们ARVD/C模型预后的作用。这些结果使我们提出了脱莫普拉蛋白在心肌细胞谱系和脱莫普拉抗缺损的子集中起着至关重要的作用的假设。 arvd/c。具体目的包括：（1）通过在不同的心肌细胞谱系中烧蚀desmoplakin来确定负责ARVD/C的心肌细胞的子集。（2）确定连接蛋白信号如何影响我们模型中的心肌细胞和心肌细胞粘附。（3）通过抑制（a）2-catenin的作用以及（b）K+离子通道和2-肾上腺素能受体，以挽救或改变我们模型中ARVD/C的进展。公共卫生相关性：该五年提案的目的是（i）了解致命人类疾病的各种临床特征的细胞机制，心律失常右心室发育不良/心肌病（ARVD/C）和（ii）研究MANIPULATION MANIPULATIT和MANED MOYERTAINT和NEW MOLEDERS对ARV ARV的影响我们对ARVD的影响，我们对ARV的影响进行了ARVD的影响。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，从而改善我们对该疾病的一般理解，并确定治疗这种致命疾病的治疗靶标。