Endothelial-to-mesenchymal transition and atherosclerosis

项目概要/摘要 这种竞争性更新是基于工作证明，内皮细胞（EC）的亚群， 动脉粥样硬化斑块经历向间充质细胞命运的转变， 炎症基因的表达和细胞外基质的重塑。这一转变是由 炎症信号传导使细胞对TGFβ敏感，然后驱动间充质命运转变。一个关键 间充质表型的结果是产生富含纤连蛋白的细胞外基质，该基质可以放大 炎症信号传导、募集白细胞和产生细胞因子。这一系列的事件因此创造了 正反馈是疾病进展和治疗抵抗的关键特征。我们在过去的工作 循环提供的证据表明，命运转换是由预先存在的易感EC的一小部分驱动的， 驱动血管壁重塑。我们的工作还阐明了基质重塑改变 整合素信号传导增强炎症途径并促进疾病进展。的总体目标 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 导致疾病的反馈机制目的1将阐明内皮异质性在小鼠和患者 动脉粥样硬化目的2将表征正常内皮细胞的疾病易感亚群。目标3将 阐明促炎性整合素信号传导在动脉粥样硬化中EC群体进化中的作用， 斑块和介导斑块进展的下游途径。

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.