Flow and endothelial signaling in acquired myxomatous valve disease

获得性粘液瘤性瓣膜疾病中的血流和内皮信号传导

基本信息

批准号：
10226236
负责人：
MARK L KAHN
金额：
$ 72.28万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2020-08-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10226236
关键词：
ADAMTS Address Adult Affect Age Biology Blood flow Canis familiaris Cardiovascular Diseases Cardiovascular system Cell Proliferation Cells Cellular biology Cleaved cell Complement DNA Sequence Alteration Deposition Development Disease Endothelial Cells Endothelium Environment Event Gene Expression Genetic Genetic Models Heart Valves Hemorrhage Homeostasis Human Incidence Individual Inherited Mesenchymal Mitral Valve Mitral Valve Prolapse Modeling Molecular Mus Pathogenesis Pathologic Pathology Pathway interactions Peptide Hydrolases Population Production Proteoglycan Proteolysis Role Signal Transduction Syndrome Testing Tetracyclines disease phenotype environmental change heart valve transplantation hemodynamics insight interstitial cell mouse genetics mouse model mutant novel paracrine prevent single-cell RNA sequencing tool transcription factor versican

项目摘要

Project Summary Myxomatous valve disease (MVD) arises in 2-3% of the human population and causes mitral valve prolapse and regurgitation. Although rare inherited forms of MVD have been identified, most cases arise in previously healthy valves in older individuals. MVD is characterized by proliferation of valve interstitial cells (VICs), increased matrix production, and TGFb signaling, but how such changes arise in previously healthy valves is unknown. We have recently demonstrated that hemodynamic shear forces direct heart valve development through expression of the flow-regulated KLF2 and KLF4 transcription factors in valve endothelial cells (VECs), but whether and how the hemodynamic environment might regulate the function of the mature heart valve has not been addressed. Our preliminary studies reveal that inducible genetic loss of KLF2 and KLF4 in mature VECs results in a MVD phenotype associated with high VEC and VIC proliferation, increased matrix deposition, and evidence of pathologic endothelial- mesenchymal transition (EndMT). Importantly, we find that similar MVD pathology is conferred by loss of blood flow across the mitral valve of transplanted hearts. These findings support a novel mechanism for MVD in which changes in hemodynamic conditions that alter VEC KLF2/4 expression give rise to acquired MVD. This proposal will test this hemodynamic mechanism for MVD using new genetic tools to examine how blood flow and KLF2/4 in VECs control the cellular biology (Aim 1) and the matrix biology (Aim 2) of the mature valve. The proposed studies are expected to provide new insight into MVD pathogenesis, the role of blood flow in adult heart valve homeostasis, and the role of pathologic EndMT in the cardiovascular disease.

项目概要粘液瘤性瓣膜疾病 (MVD) 出现在 2-3% 的人群中并导致二尖瓣脱垂和反流。尽管罕见的遗传性 MVD 形式已被已发现，大多数病例发生在老年人以前健康的瓣膜上。微血管密度是其特点是瓣膜间质细胞 (VIC) 增殖、基质增加产生和 TGFb 信号传导，但这些变化是如何在以前健康的身体中出现的阀门未知。我们最近证明了血流动力学剪切力通过流量调节 KLF2 和 KLF4 的表达直接心脏瓣膜发育瓣膜内皮细胞（VEC）中的转录因子，但是否以及如何血流动力学环境可能调节成熟心脏瓣膜的功能尚未已得到解决。我们的初步研究表明，KLF2 和 KLF2 的诱导性遗传丢失成熟 VEC 中的 KLF4 导致与高 VEC 和 VIC 相关的 MVD 表型增殖、基质沉积增加以及病理性内皮细胞的证据间质转化（EndMT）。重要的是，我们发现类似的 MVD 病理是这是由于移植心脏的二尖瓣血流减少所致。这些研究结果支持 MVD 的一种新机制，其中血流动力学的变化改变 VEC KLF2/4 表达的条件会引起获得性 MVD。这个提议将使用新的遗传工具测试这种 MVD 的血流动力学机制，以研究如何 VEC 中的血流和 KLF2/4 控制细胞生物学（目标 1）和基质生物学成熟阀门的（目标2）。拟议的研究预计将提供新的见解 MVD 发病机制、血流在成人心脏瓣膜稳态中的作用以及病理性 EndMT 在心血管疾病中的作用。