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的内皮亚群 项目摘要 正常的心脏瓣膜结构和成分是在开发过程中建立的，先天性 瓣膜畸形，例如由结构蛋白基因突变产生的畸形，如Marfan综合征 （MFS），随着时间的流逝，进行性混乱和功能障碍。粘液瓣疾病（MVD）是 以瓣膜小叶的增厚和进行性变性为特征，导致瓣膜反流 并减少心脏功能。而与血流有关的机械力在瓣膜传单上作用 在发育和疾病中，尚不清楚这些力如何影响阀结构和功能 分子水平。单细胞RNA测序（SCRNASEQ）显示瓣膜内皮细胞（VEC） 亚群位于具有不同血流谱的心脏瓣膜小叶区域。这些VEC之一 亚群表达Prox1（一种机械敏感的转录因子），但其在心脏瓣膜中的作用 发育，稳态和疾病尚不清楚。此外，Prox1表达式扩展到 在报告瓣膜反流的MF小鼠模型中，粘液瓣的层流侧的层流侧。我们 假设在心脏VEC中的表达在Wnt/β-catenin激活中，对瓣膜至关重要 传单组织在开发和维护阀结构和ECM组织中 成年人。目的是：1）确定心脏瓣膜开发和体内稳态中Prox1的要求。 2）确定粘液瓣膜中的Prox1错误定位是否有助于巨噬细胞浸润和 MVD进展。 3）确定局部化阀内皮细胞中是否需要Wnt/beta-catenin信号传导 Prox1表达和内皮结的成熟。这些研究的长期目标是定义 心脏瓣膜发育和病理重塑的机械敏感调节机制，因此 导致开发用于粘液瓣疾病的新型非手术治疗方法。