Genetic basis of arrhythmogenic right ventricular dysplasia (ARVD)

当前SCOR和提议的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，包括遗传性和获得性损伤，无论表现为肥大还是扩张。在项目3中，我们关注扩张型心肌病伴心律失常主要影响右心室的范例。致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丢失，并被脂肪和纤维组织替代，随着病情进展，导致右心室扩张和心功能受损。因此，ARVD在右心室启动，而FDCM在左心室启动。ARVD的病理从右心室延伸到左心室，这是FDCM中观察到的最初受累部位和病理扩散的镜像。其临床表现为心律失常、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细胞凋亡。虽然有四个基因位点与这种疾病有关，但没有一个致病基因被确定。我们建议确定在我们的家庭，我们最近映射到一个新的位点，3p23，使用位置候选人或位置克隆的方法负责ARVD的基因。我们将利用万维网上的物理图谱信息来确定YAC克隆和EST，它们映射到关键区域。我们将使用这种克隆材料来确定新的遗传标记，以进一步描绘该地区以及新的候选基因在我们的家庭测序。我们进一步建议在我们已经确定的一个家族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，并最终确定该基因。这些目标解决了一般假设，即识别遗传缺陷和解开家族性心肌病的分子基础将提供洞察力的基础上观察到的各种其他家族性和获得性疾病的心室衰竭的理解。此外，解开腔室特异性刺激或基因，定位和决定心室反应的右心室，而不是左心室，并阐明细胞凋亡在心脏重塑中的作用，将有重要的意义，心力衰竭的发病机制和治疗。

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.