MOLECULAR MECHANISMS OF VALVE DEVELOPMENT AND DISEASE

瓣膜发育和疾病的分子机制

• 批准号: 6772219
• 负责人: Dudley Woodrow (Woody) Benson
• 金额: $ 40.59万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6772219
• 关键词: aortic valve; artificial chromosomes; cardiogenesis; clinical research; congenital heart disorder; dogs; echocardiography; family genetics; gene expression; gene mutation; genetic library; genetic mapping; genetic markers; heart valves; high throughput technology; human subject; laboratory mouse; linkage disequilibriums; molecular cloning; molecular genetics; phenotype; polymerase chain reaction; quantitative trait loci

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.

这是一个临床项目，将研究心脏瓣膜病，一个常见的临床问题进行大量的发病率和死亡率。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。该项目的目标是使用遗传连锁定位克隆方法来确定遗传位点，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：二叶式主动脉瓣（BAV）和Ebstein异常。基因和信号通路的共性 流出道和AV管的瓣膜发育为半月瓣和AV瓣的研究提供了理论基础。一些观察结果表明，BAV和Ebstein异常都有遗传原因，但在确定易感基因座方面进展甚微。在AIM 1和AIM 2中，将对170例带BAV的心肌进行方差分量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完整临床评价。在初步研究中，已经确定了50种kinases。AIM 3是Ebstein异常的连锁位置克隆研究。由于人类适合于标测的运动尚未确定，我们研究了具有三尖瓣的狗家族 畸形（CTVM，Ebstein异常的狗类似物），并在与人类染色体17 q11 -23同源的区域中确定了狗9号染色体（CFA 9）上的易感基因座。将对50名Ebstein异常先证者进行CTVM基因人类同源物的突变分析。将使用内膜垫成熟和重塑测定在AIM 4中进行已知疾病候选基因的机制研究。这些研究是转化研究的重要组成部分，因为它们提供了一个链接到发展机制，是必不可少的定义发病机制。最终，瓣膜疾病的分类可能更多地与遗传原因和发病机制有关，而不是诊断时的临床表型。基于发病机制的瓣膜疾病分类学修订可能为开发 基于分子机制而非终末期临床表型的治疗策略。