Endothelial-to-mesenchymal transition and atherosclerosis

内皮间质转化和动脉粥样硬化

• 批准号: 10551998
• 负责人: Martin A Schwartz
• 金额: $ 83.56万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-12 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10551998
• 关键词: Appearance; Arterial Fatty Streak; Arteries; Atherosclerosis; Attention; Binding; Blood Vessels; Blood flow; Cell Proliferation; Cells; Characteristics; Cytometry; Data; Deposition; Development; Disease; Disease Progression; Disease Resistance; Endothelial Cells; Endothelium; Event; Evolution; Extracellular Matrix; Feedback; Fibronectins; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Grant; Growth; Health; Heterogeneity; Human; Image; Inflammation; Inflammatory; Integrin alpha5beta1; Integrins; Leukocytes; Life Style; Link; Machine Learning; Macrophage; Maps; Mediating; Mesenchymal; Metabolic Diseases; Minor; Molecular; Molecular Profiling; Mus; Paint; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Phenotype; Population; Predisposition; Process; Production; Proteomics; Resistance; Role; Rupture; Signal Transduction; Smooth Muscle Myocytes; Stimulus; Techniques; Therapeutic; Time; Transforming Growth Factor beta; Up-Regulation; Vascular Permeabilities; Work; advanced disease; cerebral cavernous malformations; cytokine; human tissue; immunocytochemistry; mouse model; novel; programs; recruit; repaired; response; single-cell RNA sequencing; therapeutic target; therapy resistant; tool; vascular inflammation

Project Summary/Abstract This competitive renewal is based on work demonstrating that a subpopulation of endothelial cells (ECs) in atherosclerotic plaques undergo a transition to a mesenchymal cell fate that involves loss of barrier function, expression of inflammatory genes and remodeling of the extracellular matrix. This transition is initiated by inflammatory signaling that sensitizes cells to TGFβ, which then drives the mesenchymal fate transition. A key consequence of the mesenchymal phenotype is production of a fibronectin-rich extracellular matrix that amplifies inflammatory signaling, recruiting leukocytes and production of cytokines. This sequence of events thus creates positive feedback, a key feature of disease progression and resistance to therapy. Our work during the past grant cycle has provided evidence that fate switching is driven by a minor subset of pre-existing, susceptible ECs that drive vessel wall remodeling. Our work has also elucidated novel pathways by which matrix remodeling alters integrin signaling to enhance inflammatory pathways and promotes disease progression. The overall goal of the current application is to understand the EC subpopulations and factors that drive fate switching, and the positive feedback mechanisms that drive disease. Aim 1 will elucidate endothelial heterogeneity in mice and in patients with atherosclerosis. Aim 2 will characterize disease-prone subset of normal endothelial cells. Aim 3 will elucidate the role of pro-inflammatory integrin signaling in evolution of EC populations in the atherosclerotic plaque and the downstream pathways that mediate plaque progression.

项目摘要/摘要 这种竞争性更新是基于工作表明内皮细胞（EC）在 动脉粥样硬化斑块经历涉及屏障功能丧失的间充质细胞脂肪的过渡， 炎症基因的表达和细胞外基质的重塑。这种过渡是由 炎症信号传导将细胞感应到TGFβ，然后驱动间充质命运转变。钥匙 间质表型的结果是产生富含纤连蛋白的细胞外基质 炎症信号传导，募集白细胞和细胞因子的产生。因此，这一系列事件创造了 积极反馈，疾病进展和对治疗的抵抗力的关键特征。我们过去的工作 周期提供了证据，表明命运转换是由一个较小的先前存在的易感EC的子集驱动的 驱动容器墙改造。我们的工作还阐明了矩阵重塑改变的新型途径 整合素信号传导以增强炎症途径并促进疾病进展。总体目标 当前的应用是了解驱动命运转换的EC亚群和因素，以及积极的 驱动疾病的反馈机制。 AIM 1将阐明小鼠和患者的内皮异质性 动脉粥样硬化。 AIM 2将表征正常内皮细胞的易于疾病的子集。目标3意志 阐明促炎性整联蛋白信号在动脉粥样硬化中EC种群进化中的作用 斑块和介导斑块进展的下游途径。