MOLECULAR MECHANISMS OF VALVE DEVELOPMENT AND DISEASE

这是一个研究瓣膜心脏病的临床项目，瓣膜心脏病是一种常见的临床问题，具有相当高的发病率和死亡率。瓣膜畸形通常被认为是出生缺陷，越来越多的证据表明，在生命后期发现的瓣膜疾病也可能起源于瓣膜形成过程。该项目的目标是使用遗传连锁-定位克隆的方法来识别遗传位点，并最终确定人类基因突变的身份。重点是两种类型的心脏瓣膜病：二尖瓣主动脉瓣(BAV)和Ebstein畸形。基因和信号通路的共性 流出道和房室管在瓣膜发育方面的研究为半月瓣和房室瓣的研究提供了理论基础。一些观察表明，BAV和Ebstein异常都有遗传原因，但在识别易感基因座方面进展甚微。在AIM 1和AIM 2中，将对170个BAV家系进行方差成分连锁分析和位置克隆研究，参与者将接受包括超声心动图在内的全面临床评估。在初步研究中，已经确定了50个品种。目的3是对Ebstein异常的连锁定位克隆研究。由于还没有鉴定出适合作图的人类血统，我们研究了一种带有三尖瓣的犬种。 在狗的9号染色体(CFA9)上，在与人类染色体17q11-23同源的区域发现了一个易感基因。将对50例有Ebstein异常的先证者进行CTVM基因人类同源物的突变分析。已知的疾病候选基因的机制研究将在AIM 4中使用心内膜垫成熟和重塑分析进行。这类研究是翻译研究的重要组成部分，因为它们提供了与定义发病机制必不可少的发育机制的联系。最终，瓣膜病的分类可能更多地与遗传原因和发病机制有关，而不是与诊断时的临床表型有关。基于发病机制的修订的瓣膜疾病分类可能提供发展的机会 基于分子机制而不是终末期临床表型的治疗策略。

This is a clinical project that will study valvular heart disease, a common clinical problem carrying substantial morbidity and mortality. Valve malformations are frequently recognized as birth defects, and a growing body of evidence suggests that valve disease discovered later in life may also have origins during valvulogenesis. The objective of this project is to use a genetic linkage-positional cloning approach to identify genetic loci and ultimately ascertain the identity of gene mutations in humans. The emphasis is on two types of valvular heart disease: bicuspid aortic valve (BAV) and Ebstein anomaly. The commonality of genes and signal pathways in valve development of both the outflow tract and the AV canal provides a rationale for the study of both the semilunar and AV valves. Several observations suggest that both BAV and Ebstein anomaly have a genetic cause, but little progress has been made toward identifying susceptibility loci. In AIM 1 and AIM 2 variance component linkage analysis and positional cloning studies will be performed on 170 kindreds with BAV, participants will undergo complete clinical evaluation including echocardiography. In preliminary studies, 50 kindreds have already been identified. AIM 3 is a linkage-positional cloning study of Ebstein anomaly. Since human kindreds suitable for mapping have not been identified, we studied a dog kindred with tricuspid valve malformation (CTVM, the dog analog of Ebstein anomaly) and identified a susceptibility locus on dog chromosome 9 (CFA9) in a region homologous to human chromosome 17q11-23. Mutation analysis of the human homolog of the CTVM gene will be carried out in 50 probands with Ebstein anomaly. Mechanistic studies of known disease candidate genes will be performed in AIM 4 using an endocardial cushion maturation and remodeling assay. Such studies are an essential component of translational research as they provide a link to developmental mechanisms that are essential for defining pathogenesis. Ultimately the taxonomy of valve disease may relate more to genetic cause and pathogenetic mechanism than to clinical phenotype at the time of diagnosis. A revised valve disease taxonomy based on pathogenesis may provide opportunities to develop therapeutic strategies founded on molecular mechanisms rather than end-stage clinical phenotype.