Molecular Mechanisms of Aortic Valve Formation

 描述（由申请人提供）：先天性心脏病是最常见的出生缺陷类型，是生命第一年死亡的主要非感染性原因。主动脉瓣畸形可以说是最常见的心脏畸形类型，因为二叶式主动脉瓣在人群中的估计患病率为1-2%。主动脉瓣畸形发生的机制尚不清楚。我们是第一个报道NOTCH 1杂合突变与人类二叶式主动脉瓣相关的人，但我们对主动脉瓣畸形发生机制的理解仍然存在重大空白。我们已经产生了一个新的小鼠模型的高度渗透性主动脉瓣畸形（二叶式主动脉瓣）使用Notch 1杂合子小鼠回交到一个Nos 3（内皮型一氧化氮合酶）空背景。这些小鼠显示出近100%的主动脉瓣异常发生率，包括增厚、二叶和功能障碍的主动脉瓣。我们的初步研究表明，Nos 3基因与Notch 1在瓣膜内皮细胞相互作用，导致瓣膜狭窄。另外的研究表明，Nos 3的缺失抑制了内皮细胞中Notch 1信号传导，从而通过表观遗传机制引起瓣膜缺陷。总体假设是，内皮细胞谱系中Notch 1的缺乏通过破坏发育中的主动脉瓣垫间充质的重塑而导致BAV。在这个建议中，我们将阐明细胞和分子异常，在这个临床相关模型的主动脉瓣畸形。该提案的具体目标是：具体目标1。明确二叶式主动脉瓣形成的细胞和分子机制。具体目标2。确定Notch 1信号传导对正常主动脉瓣形态发生的细胞谱系要求。具体目标3。确定一氧化氮在主动脉瓣重塑中调节Notch 1的机制。

 DESCRIPTION (provided by applicant): Congenital heart disease is the most common type of birth defect and is the leading non-infectious cause of death in the first year of life. Malformations of the aortic valves are arguably the most common type of cardiac malformation as bicuspid aortic valve alone has an estimated prevalence of 1-2% in the population. The mechanisms underlying the development of aortic valve abnormalities are not well understood. We were the first to report that heterozygous mutations in NOTCH1 were associated with bicuspid aortic valve in humans but there remains a major void in our understanding of the mechanisms by which aortic valve malformations occur. We have generated a new mouse model of highly penetrant aortic valve malformations (bicuspid aortic valve) using Notch1 heterozygote mice backcrossed into a Nos3 (endothelial nitric oxide synthase)-null background. These mice display a near 100% incidence of aortic valve abnormalities including thickened, bicuspid and dysfunctional aortic valves. Our preliminary studies suggest that Nos3 genetically interacts with Notch1 in the valve endothelium to cause valve stenosis. Additional studies suggest that loss of Nos3 inhibits Notch1 signaling in endothelial cells to cause valve defects by an epigenetic mechanism. The overall hypothesis is that deficiency of Notch1 in endothelial cell lineages leads to BAV by disrupting the remodeling of developing aortic valve cushion mesenchyme. In this proposal, we will elucidate the cellular and molecular abnormalities in this clinically relevant model of aortic valve malformations. The specific aims of the proposal are: Specific Aim 1. To define the cellular and molecular mechanisms underlying the development of bicuspid aortic valve. Specific Aim 2. To determine the cell lineage requirement for Notch1 signaling for normal aortic valve morphogenesis. Specific Aim 3. To determine the mechanisms by which nitric oxide regulates Notch1 in the remodeling aortic valve.