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: 6564979
• 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: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6564979
• 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 和拟议更新的总体目标是阐明心脏对遗传性和后天性损伤（无论表现为肥大还是扩张）的长期适应性反应的分子基础。在项目 3 中，我们重点关注主要影响右心室的扩张型心肌病伴心律失常的范例。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，其特征是心肌细胞逐渐丧失并被脂肪和纤维组织取代，随着病情的发展，导致右心室扩张和心功能受损。因此，ARVD 是在右心室启动的，而 FDCM 是在左心室启动的。 ARVD 的病理从右心室延伸至左心室，这与 FDCM 中观察到的初始受累部位和病理扩散都是镜像。临床病程以心律失常、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造成的。尽管有四个基因位点与该疾病相关，但尚未确定任何致病基因。我们建议鉴定我们家族中导致 ARVD 的基因，我们最近使用位置候选或位置克隆方法将其映射到一个新的基因座 3p23。我们将使用万维网上提供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材料来识别新的遗传标记，以进一步描绘该区域以及要在我们的家族中进行测序的新候选基因。我们进一步建议在我们已鉴定的一个家族中绘制一个与任何已知的 ARVD 基因座无关的新基因座，并最终鉴定该基因。这些目标解决了一个普遍的假设，即识别遗传缺陷并揭示家族性心肌病的分子基础将为理解因各种其他家族性和获得性疾病而观察到的心室衰竭提供基础见解。此外，解开定位和决定右心室（而不是左心室）心室反应的心室特异性刺激或基因，并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产生重要影响。