Functional diversity of lung pericytes in lung injury

摘要 周细胞与肺损伤和许多器官的修复有关。我们的研究集中在 肺间质亚群在组织损伤和修复中的作用，我们最近的工作揭示了肺周细胞 在受伤期间可能有多种功能作用。来自活化肺的转录组学分析的数据 周细胞揭示参与炎症、血管生成和基质的多个基因的上调 重塑本项目的目标是表征周细胞在其反应中的功能多样性 肺损伤的临床相关模型-流感感染。为了实现这一目标，我们将测试 关于周细胞在内皮和免疫调节中的作用的假说。在目标1中，我们将研究 周细胞-内皮细胞串扰的机制，导致内皮细胞的激活和增加 肺通透性血管生成素-L4（ANGPTL4）被认为是一种高通透性因子， 在我们的初步研究中也在活化的肺周细胞中高度上调。我们将研究周细胞- 衍生的ANGPTL4在此目的中影响肺内皮功能。在目标2中，我们将评估肺的作用 周细胞运输炎性单核细胞。在流感感染的鼠模型中， 单核细胞与肺损伤的发生有关。炎症单核细胞的募集 在流感中通过CC-趋化因子受体2（CCR 2）依赖性机制发生。我们的工作表明 活化的周细胞高度上调CCL2，CCR2的主要配体。我们将评估功能 周细胞衍生的CCL2和其他CCR2配体在炎症单核细胞募集中的作用。最后在 目的3，我们将使用单核转录组学技术来表征周细胞群中的功能亚群， 接近。这一目标的提出将提供深入了解肺周细胞的不同功能状态 在流感感染的整个过程中，以及介导肺损伤的功能亚型。

ABSTRACT Pericytes have been implicated in lung injury and repair in a number of organs. Our research focuses on the role of lung stromal subpopulations in tissue injury and repair, and our recent work revealed lung pericytes may have multiple functional roles during injury. Data from transcriptomic analyses of activated lung pericytes reveal upregulation of multiple genes involved in inflammation, angiogenesis, and matrix remodeling. The goal of this project is to characterize the functional diversity of pericytes in their response to a clinically relevant model of lung injury – influenza infection. To achieve this goal, we will test hypotheses on the roles of pericytes in endothelial and immune regulation. In Aim 1, we will investigate the mechanisms of pericyte-endothelial cell crosstalk that lead to activation of endothelial cells and increased lung permeability. Angiopoietin-L4 (ANGPTL4) has been implicated as a hyperpermeability factor that is also highly upregulated in activated lung pericytes in our preliminary studies. We will examine how pericyte- derived ANGPTL4 affects lung endothelial function in this aim. In Aim 2, we will evaluate the role of lung pericytes in trafficking inflammatory monocytes. In murine models of influenza infection, inflammatory monocytes have been implicated in the development of lung injury. Recruitment of inflammatory monocytes in influenza occurs through a CC-chemokine receptor 2 (CCR2) dependent mechanism. Our work shows that activated pericytes highly upregulate CCL2, a major ligand for CCR2. We will evaluate the functional role of pericyte-derived CCL2, and other CCR2 ligands, in inflammatory monocyte recruitment. Finally, in Aim 3, we will characterize functional subsets in the pericyte population using single nucleus transcriptomic approaches. This proposed aim will provide insight into the diverse functional states of lung pericytes throughout the course of influenza infection and functional subtypes that mediate lung injury.