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: 10418935
• 负责人: Arno Wessels
• 金额: $ 48.78万
• 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/10418935
• 关键词: Area; BMPR1A gene; Birth; Bone Morphogenetic Proteins; Cell Lineage; Cells; Collagen Type IV; 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; 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（EPDCs）在形成中的作用