Endothelial subpopulations in heart valve development and congenital heart disease

心脏瓣膜发育和先天性心脏病中的内皮亚群

• 批准号: 10521286
• 负责人: Katherine E Yutzey
• 金额: $ 48.51万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10521286
• 关键词: Ablation; Adhesions; Adult; Affect; Blood flow; Crystalline Lens; Data Set; Development; Disease; Disease Progression; Endothelial Cells; Endothelium; Exposure to; Extracellular Matrix; FOXC2 gene; Family suidae; Functional disorder; Gene Expression; Gene Proteins; Genes; Goals; Heart Valves; Homeobox; Homeostasis; Human; Infiltration; Liquid substance; Liver; Lymphatic System; Macrophage; Maintenance; Marfan Syndrome; Mitral Valve; Molecular; Morphogenesis; Morphology; Mus; Mutation; Pancreas; Pathologic; Patients; Permeability; Population; Reporting; Role; Side; Signal Induction; Signal Transduction; Stratification; Structural Protein; Structure; Tamoxifen; Therapeutic; Time; aortic valve; beta catenin; congenital heart disorder; connexin 37; fluid flow; heart function; lymphatic valve; malformation; mechanical force; mouse model; neuron development; novel therapeutics; prevent; single-cell RNA sequencing; transcription factor; transcriptome sequencing

Endothelial Subpopulations in Heart Valve Development and Congenital Disease Project Summary Normal heart valve structure and composition are established during development, and congenital valve malformations, such as those arising from mutations in structural protein genes as in Marfan syndrome (MFS), have progressive disorganization and dysfunction over time. Myxomatous valve disease (MVD) is characterized by thickening and progressive degeneration of valve leaflets, leading to valvular regurgitation and reduced heart function. While fluctuating mechanical forces related to blood flow act on the valve leaflets in development and disease, it is not known how these forces affect valve structure and function at the molecular level. Single cell RNA sequencing (scRNAseq) demonstrated valve endothelial cell (VEC) subpopulations localized in regions of heart valve leaflets with distinct blood flow profiles. One of these VEC subpopulations expresses Prox1, a mechanosensitive transcription factor, but its roles in heart valve development, homeostasis, and disease are unknown. Moreover, Prox1 expression is expanded to the laminar flow side of myxomatous valves in a mouse model of MFS with reported valve regurgitation. We hypothesize that Prox1 expression in heart VECs, subject to Wnt/β-catenin activation, is critical for valve leaflet organization during development and for maintenance of valve structure and ECM organization in adults. The Aims are: 1) Determine the requirements for Prox1 in heart valve development and homeostasis. 2) Determine if Prox1 mislocalization in myxomatous valve leaflets contributes to macrophage infiltration and MVD progression. 3) Determine if Wnt/beta-catenin signaling in valve endothelial cells is required for localized Prox1 expression and endothelial junction maturation. The long-term goals of these studies are to define mechanosensitive regulatory mechanisms of heart valve development and pathologic remodeling, thus leading to the development of new nonsurgical therapeutic approaches for myxomatous valve disease.

心脏瓣膜发育和先天性疾病中的内皮细胞亚群 项目摘要 正常的心脏瓣膜结构和组成是在发育过程中建立的， 瓣膜畸形，如马凡氏综合征中结构蛋白基因突变引起的瓣膜畸形 (MFS)随着时间的推移，会出现渐进性的组织混乱和功能障碍。粘液瘤性瓣膜病（MVD）是 以瓣膜小叶增厚和进行性退化为特征，导致瓣膜返流 心脏功能下降当与血流相关的波动机械力作用在瓣叶上时， 在发育和疾病中，尚不清楚这些力如何影响瓣膜的结构和功能。 分子水平。单细胞RNA测序（scRNAseq）证实瓣膜内皮细胞（VEC） 位于具有不同血流轮廓的心脏瓣膜小叶区域的亚群。其中一个VEC Prox 1是一种机械敏感性转录因子，但它在心脏瓣膜中的作用 发育、体内平衡和疾病是未知的。此外，Prox 1表达式被扩展到 MFS小鼠模型中粘液瘤瓣膜的层流侧，报告了瓣膜返流。我们 假设在心脏VECs中，受Wnt/β-catenin激活，Prox 1表达对于瓣膜 用于维持瓣膜结构和ECM组织， 成年人了目的：1）确定心脏瓣膜发育和稳态对Prox 1的要求。 2)确定粘液瘤性瓣膜小叶中的Prox 1错误定位是否有助于巨噬细胞浸润， MVD进展。3)确定瓣膜内皮细胞中的Wnt/β-连环蛋白信号传导是否是局部 Prox 1表达和内皮连接成熟。这些研究的长期目标是确定 心脏瓣膜发育和病理性重塑的机械敏感性调节机制，因此 导致粘液瘤性瓣膜病的新的非手术治疗方法的发展。