Endothelial-to-mesenchymal transition and atherosclerosis

项目摘要/摘要 这种竞争性更新的基础是研究表明，在 动脉粥样硬化斑块经历了向间充质细胞命运的过渡，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。这一过渡是由 炎症信号使细胞对转化生长因子β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维连接蛋白的细胞外基质，从而放大 炎症信号、募集白细胞和细胞因子的产生。因此，这一系列事件产生了 正反馈，疾病进展和抗拒治疗的一个关键特征。我们在过去拨款期间所做的工作 Cycle提供的证据表明，命运转换是由预先存在的、易受影响的EC的一小部分驱动的，这些EC 推动血管壁重塑。我们的工作还阐明了基质重塑改变的新途径 整合素信号增强炎症途径，促进疾病进展。该计划的总体目标 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 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 动脉粥样硬化。目标2将描述正常内皮细胞中易患疾病的亚群。目标3将 阐明致炎整合素信号在动脉粥样硬化EC群体进化中的作用 斑块及其下游调节斑块进展的途径。

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.