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

基本信息

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
项目类别：
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

项目摘要

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亚群项目概要正常的心脏瓣膜结构和组成是在发育过程中建立的，先天性的瓣膜畸形，例如由结构蛋白基因突变引起的瓣膜畸形，如马凡综合征 (MFS)，随着时间的推移会出现进行性紊乱和功能障碍。其特点是瓣叶增厚和进行性退化，导致瓣膜反流心脏功能下降，而与血流相关的波动机械力作用在瓣叶上。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的单细胞RNA测序（scRNAseq）证明了瓣膜内皮细胞（VEC）位于具有不同血流特征的心脏瓣膜小叶区域的亚群。亚群表达 Prox1，一种机械敏感转录因子，但其在心脏瓣膜中的作用此外，Prox1 的表达范围扩大到了发育、稳态和疾病。报告有瓣膜反流的 MFS 小鼠模型中粘液瘤瓣膜的层流侧。很快发现，心脏 VEC 中的 Prox1 表达（受 Wnt/β-连环蛋白激活）对于瓣膜至关重要开发期间的传单组织以及用于维护瓣膜结构和 ECM 组织目标是： 1) 确定 Prox1 在心脏瓣膜发育和稳态中的要求。 2) 确定 Prox1 在粘液瘤瓣叶中的错误定位是否有助于巨噬细胞浸润和 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化所必需的。 Prox1 表达和内皮连接成熟是这些研究的长期目标。心脏瓣膜发育和病理重塑的机械敏感调节机制，因此导致了粘液瘤性瓣膜疾病新的非手术治疗方法的开发。