Genetic basis of arrhythmogenic right ventricular dysplasia (ARVD)

当前SCOR和拟议更新的总体目标是阐明心脏对损伤的长期适应性反应的分子基础，无论是遗传性的还是获得性的，无论是表现为肥大还是稀释。在项目3中，我们主要关注扩张型心肌病与心律失常主要影响右心室的范例。心律失常性右心室发育不良（ARVD）是一种病因不明的家族性心肌病，其特征是肌细胞逐渐减少，取而代之的是脂肪和纤维组织，随着病程的发展，导致右心室萎缩和心功能受损。因此，ARVD起源于右心室，而FDCM起源于左心室。ARVD的病理从右心室扩展到左心室，这是FDCM中观察到的最初受累部位和病理扩散的镜像。临床过程以心律失常、猝死和心力衰竭为特征，心肌细胞死亡并被脂肪纤维组织取代的过程是由于细胞凋亡引起的。尽管有四个基因位点与此病有关，但尚未发现任何致病基因。我们建议在我们的家族中鉴定负责ARVD的基因，我们最近将其定位到一个新的位点，3p23，使用位置候选或位置克隆方法。我们将使用万维网上提供的物理制图信息来识别映射到关键区域的YAC克隆和est。我们将利用这些克隆材料来鉴定新的遗传标记，以进一步划定该区域，并在我们的家庭中对新的候选基因进行测序。我们进一步建议在我们已经确定的家族中绘制一个与任何已知的ARVD位点无关的新位点，并最终确定该基因。这些目标解决了一个普遍的假设，即识别遗传缺陷和揭示家族性心肌病的分子基础，将为理解在各种其他家族性和获得性疾病中观察到的心室衰竭提供基本的见解。此外，揭示定位并决定右心室（而非左心室）心室反应的腔室特异性刺激或基因，阐明细胞凋亡在心脏重塑中的作用，将对心力衰竭的发病机制和治疗具有重要意义。

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.