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：
10408810
负责人：
MARK L KAHN
金额：
$ 71.72万
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/10408810
关键词：
ADAMTS Address Adult Affect Age Biology Blood flow Canis familiaris Cardiovascular Diseases Cardiovascular system Cell Proliferation Cells Cellular biology 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

ADAMTS Address Adult Affect Age Biology Blood flow Canis familiaris Cardiovascular Diseases Cardiovascular system Cell Proliferation Cells Cellular biology 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

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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.

项目摘要粘液瓣疾病（MVD）出现在2-3％的人口中，原因二尖瓣脱垂和反流。虽然MVD的罕见形式是确定的，大多数情况在老年人的先前健康瓣膜中产生。 MVD是以瓣膜间质细胞（VIC）的增殖为特征，矩阵增加生产和TGFB信号传导，但是这种变化是如何在以前健康的阀门未知。我们最近证明了血液动力学剪切力通过表达流动调节的KLF2和KLF4的直接心脏瓣膜发育瓣膜内皮细胞（VEC）中的转录因子，但是否以及如何血液动力学环境可能调节成熟心脏瓣膜的功能已解决。我们的初步研究表明，KLF2和成熟vec中的KLF4导致与高VEC和VIC相关的MVD表型增殖，基质沉积增加和病理内皮的证据间充质转变（ENDMT）。重要的是，我们发现类似的MVD病理是由移植心脏的二尖瓣瓣膜流失的流失所赋予。这些发现支持一种新型MVD机制，其中血液动力学变化改变VEC KLF2/4表达的条件会引起获得的MVD。这个建议将使用新的遗传工具测试MVD的血流动力学机制 VEC中的血流和KLF2/4控制细胞生物学（AIM 1）和基质生物学（AIM 2）成熟阀门。预计拟议的研究将提供新的见解进入MVD发病机理，血流在成人心脏瓣膜稳态中的作用，以及病理EndMT在心血管疾病中的作用。