Role of the Epicardium in Valve Development and Valve Disease

心外膜在瓣膜发育和瓣膜疾病中的作用

• 批准号: 10597222
• 负责人: Arno Wessels
• 金额: $ 48.82万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597222
• 关键词: Area; BMPR1A gene; Birth; Bone Morphogenetic Proteins; Cell Lineage; Cells; Collagen Type IV; Compensation; Development; Disease; Embryo; Endocardium; Epicardium; Event; Extracellular Matrix; Goals; Growth Factor; Health; Heart; Human; Integrin alpha4; Knock-out; Lateral; Life; MMP2 gene; Mesenchymal; Mitral Valve; Mitral Valve Insufficiency; Mitral Valve Prolapse; Modeling; Mus; Parietal; Pathogenesis; Pathway interactions; Patients; Pattern; Phenotype; Process; Proliferating; Publications; Publishing; Reporting; Research Proposals; Role; Series; Signal Transduction; Testing; Time; Vascular Cell Adhesion Molecule-1; bone morphogenetic protein receptors; insight; migration; postnatal; transcription factor

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.

在这个项目中，我们的目标是确定心外膜衍生细胞 (EPDC) 在形成中的作用 房室（AV）瓣膜并研究其在发病机制中的潜在作用 粘液瘤性瓣膜疾病（MVD）。几年前，我们发表了一项研究，其中描述了 房室 (AV) 交界处的 EPDC 如何形成一组特定的 AV 小叶 阀门。为了深入了解这些事件是如何调控的，我们最初关注生长因子 通过骨形态发生蛋白 (BMP) 途径发出信号。我们删除了 BMP 受体 使用心外膜特异性 WT1cre 小鼠从心外膜细胞谱系中提取 ALK3/BMPR1A。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，瓣膜 形成粘液瘤瓣膜表型，让人想起在患者中观察到的情况 遭受MVD。从心外膜细胞谱系中删除转录因子 SOX9 会导致类似的结果 结果。该项目的目标是确定调节 AV-迁移的机制 将 EPDC 植入顶叶 AV 瓣叶，以确定 AV-EPDC 如何调节 AV 瓣膜 发展，并阐明其在二尖瓣疾病发病机制中的作用。