Endothelial-to-mesenchymal transition and atherosclerosis

内皮间质转化和动脉粥样硬化

• 批准号: 9973898
• 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/9973898
• 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; Mediating; Mesenchymal; Metabolic Diseases; Minor; Molecular; Molecular Profiling; Mus; Paint; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Phenotype; Population; 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; base; cerebral cavernous malformations; cytokine; human tissue; immunocytochemistry; macrophage; 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.

项目概要/摘要 这种竞争性更新的基础是证明内皮细胞 (EC) 亚群 动脉粥样硬化斑块经历向间充质细胞命运的转变，其中涉及屏障功能的丧失， 炎症基因的表达和细胞外基质的重塑。这一转变是由 炎症信号使细胞对 TGFβ 敏感，然后驱动间充质命运转变。一把钥匙 间充质表型的结果是产生富含纤连蛋白的细胞外基质，从而放大 炎症信号传导、募集白细胞和细胞因子的产生。这一系列事件因此创造了 正反馈，疾病进展和治疗抵抗的一个关键特征。我们在过去的资助期间所做的工作 周期提供的证据表明，命运转换是由一小部分预先存在的易受影响的 EC 驱动的，这些 EC 是 驱动血管壁重塑。我们的工作还阐明了矩阵重塑改变的新途径 整合素信号传导增强炎症途径并促进疾病进展。该项目的总体目标是 目前的应用是了解EC亚群和驱动命运转换的因素，以及积极的影响 驱动疾病的反馈机制。目标 1 将阐明小鼠和患者的内皮异质性 患有动脉粥样硬化。目标 2 将描述正常内皮细胞的易患病亚群的特征。目标3将 阐明促炎性整合素信号在动脉粥样硬化 EC 群体进化中的作用 斑块和介导斑块进展的下游途径。