Role of the Epicardium in Valve Development and Valve Disease

在这个项目中，我们的目标是确定心外膜衍生细胞（EPDCs）在形成中的作用， 的房室（AV）瓣膜，并探讨其在发病机制中的潜在作用， 粘液瘤性瓣膜病（MVD）。几年前，我们发表了一项研究， 房室（AV）交界处的EPDC如何促成AV的特定小叶组 阀门.为了深入了解这些事件是如何调节的，我们最初关注生长因子 通过骨形态发生蛋白（BMP）通路进行信号传导。我们删除了BMP受体 使用心外膜特异性WT 1cre小鼠从心外膜细胞谱系中分离ALK 3/BMPR 1A。我们 观察到这导致AV连接处的异常，包括 侧瓣叶中AV-EPDC的数量。我们还发现，出生后， 出现了粘液瘤样瓣膜表型，这让人想起在患者中观察到的情况。 患有微血管病从心外膜细胞谱系中删除转录因子SOX 9导致类似的 结果该项目的目标是确定调节AV-1迁移的机制， EPDCs进入顶叶AV瓣叶，以确定AV-EPDCs如何调节AV瓣 发展，并阐明其在二尖瓣疾病发病机制中的作用。

In this project we aim to determine the role of epicardially-derived cells (EPDCs) in the formation of the atrioventricular (AV) valves and to investigate their potential role in the pathogenesis of myxomatous valve disease (MVD). A few years ago, we published a study in which we described how EPDCs at the atrioventricular (AV) junction contribute to a specific set of leaflets of the AV valves. To obtain insight into how these events are regulated, we initially focused on growth factor signaling through the Bone Morphogenetic Protein (BMP) pathway. We deleted the BMP receptor ALK3/BMPR1A from the epicardial cell lineage using the epicardial-specific WT1cre mouse. We observed that this led to abnormalities at the AV junction, including a significant decrease in the number of AV-EPDCs in the lateral valve leaflets. We also found that, after birth, the valves developed a myxomatous valve phenotype, reminiscent of that being observed in patients suffering MVD. Deleting the transcription factor SOX9 from the epicardial cell lineage led to similar results. The goals of this project are to determine the mechanisms regulating the migration of AV- EPDCs into the parietal AV valve leaflet, to establish how AV-EPDCs regulate AV valve development, and to elucidate their role in the pathogenesis of mitral valve disease.