Genetic basis of arrhythmogenic right ventricular dysplasia (ARVD)

致心律失常性右心室发育不良（ARVD）的遗传基础

• 批准号: 6423885
• 负责人: Robert E Roberts
• 金额: $ 18.5万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2002-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6423885
• 关键词: apoptosis; arrhythmia; cell line; cellular pathology; clinical research; family genetics; gene mutation; genetic mapping; genetic markers; heart disorder diagnosis; human genetic material tag; human subject; idiopathic dilated cardiomyopathy; myocardium disorder; nucleic acid sequence; polymerase chain reaction

The overall objective of the current SCOR and the PROPOSED RENEWAL is to elucidate the molecular basis for the long-term adaptive response of the heart to injury, both inherited and acquired, whether manifested by hypertrophy or dilitation. In Project 3 we focus on the paradigm of dilated cardiomyopathy with arrhythmias affecting primarily the right ventricle. Arrhythmogenic right ventricular dysplasia (ARVD), is a familial cardiomyopathy of unknown etiology characterized by a gradual loss of myocytes and replacement by fatty and fibrous tissue which, as it progresses, leads to dilitation of the right ventricle and impaired cardiac function. Thus, ARVD is initiated in the right ventricle in contrast to FDCM which is initiated in the left ventricle. The pathology of ARVD extends from the right ventricle to involve the left ventricle which is a mirror image to both the initial site of involvement and the spread of pathology observed in FDCM. The clinical course is characterized by arrhythmias, sudden death, and heart failure, process whereby myocardial cells die and are replaced by fatty-fibrous tissue is due to apoptosis Although four genetic loci are associated with this disease, none of the causative genes have been identified. We propose to identify the gene responsible for ARVD in our family which we recently mapped to a novel loci, 3p23, using either a positional candidate or positional cloning approach. We will use physical mapping information available on the World Wide Web to identify YAC clones and ESTs which map to the critical regions. We will use this cloned material to identify new genetic markers to further delineate the region as well as new candidate genes to be sequenced in our families. We further propose to map a novel locus in a family we have identified that is not linked to any known ARVD locus and ultimately to identify that gene as well. These objectives address the general hypothesis that identifying genetic defects and unraveling the molecular basis for familial cardiomyopathies will provide insight fundamental to the understanding of ventricular failure observed in response to a variety of other familial and acquired diseases. Additionally, unraveling the chamber specific stimuli or gene that localizes and determines the ventricular response in the right as opposed to the left ventricle and elucidating the role of apoptosis in heart remodeling will have important implications for the pathogenesis and treatment of heart failure.

当前SCOR的总体目标和提议的续签是阐明心脏对损伤的长期自适应反应的分子基础，无论是遗传和肥胖表现出来的。在项目3中，我们关注扩张心肌病的范式，心律不齐主要影响右心室。心律不齐的右心室发育不良（ARVD）是一种家族性心肌病的病因，其特征是肌细胞逐渐丧失和脂肪和纤维组织的替代，随着它的发展，它会导致右心室和心脏功能受损的稀释。因此，与在左心室中启动的FDCM相比，ARVD在右心室中启动。 ARVD的病理从右心室延伸到左心室，这是镜像的镜像，既是参与的初始部位又是在FDCM中观察到的病理的传播。临床过程的特征是心律不齐，猝死和心力衰竭，心肌细胞死亡并被脂肪 - 纤维组织取代的过程是由于凋亡引起的，尽管有四个遗传基因座与该疾病有关，但未鉴定出任何病因基因。我们建议使用位置候选者或位置克隆方法来识别我们最近对家族中ARVD的基因。我们将使用万维网上可用的物理映射信息来识别映射到关键区域的YAC克隆和EST。我们将使用这种克隆的材料来识别新的遗传标记，以进一步描述该地区以及在我们家庭中测序的新候选基因。我们进一步建议在我们确定的家庭中绘制一个新的基因座，该基因座与任何已知的ARVD基因座无关，并最终也确定该基因。这些目标解决了一个普遍的假设，即鉴定遗传缺陷并揭示家族性心肌病的分子基础将为理解对响应其他各种家族性和获得性疾病的心室衰竭的理解提供洞察力。另外，与左心室中的室内刺激或基因揭开室特异性刺激或基因相比，与左心室相比，阐明凋亡在心脏重塑中的作用将对心脏衰竭的发病机理和治疗具有重要意义。