Inflammatory Cytokines Promotes Pro-Fibrotic Thy-1 Negative Fibroblast Subpopulations In Lung Fibrosis

炎症细胞因子促进肺纤维化中促纤维化 Thy-1 阴性成纤维细胞亚群

• 批准号: 9759526
• 负责人: Daniel Abebayehu
• 金额: $ 6.61万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9759526
• 关键词: ATAC-seq; Acute; Adaptor Signaling Protein; Affect; American; Atomic Force Microscopy; Automobile Driving; Bleomycin; Cells; Characteristics; Chromatin; Chronic; Communication; Contractile Proteins; Core Biopsy; Data; Disease; Disease Progression; Epigenetic Process; Extracellular Matrix; Extracellular Matrix Proteins; Fibroblasts; Fibrosis; Flow Cytometry; Genetic Transcription; Heterogeneity; Human; Image; Immune; Infiltration; Inflammation; Inflammatory; Integrins; Interleukin-1; Interleukin-1 beta; Knockout Mice; Knowledge; Lung; Measures; Mechanics; Mediating; Methods; Modeling; Myofibroblast; Optics; Pathogenesis; Population; Production; Publishing; Pulmonary Fibrosis; Role; Signal Transduction; TNF gene; TNFRSF1A gene; Testing; Therapeutic Intervention; Time; Tissues; Vesicle; Work; candidate marker; cytokine; epigenetic regulation; fibrogenesis; idiopathic pulmonary fibrosis; innovation; mechanotransduction; mouse model; novel; novel strategies; programs; promoter; recruit; targeted treatment; transcriptome sequencing

Idiopathic pulmonary fibrosis (IPF) is a fatal disease with no clear pathogenesis or cure. It is characterized by chronic inflammatory cell infiltration, elevated inflammatory cytokines, myofibroblast accumulation, and aberrant extracellular matrix (ECM) remodeling. Fibroblastic foci, the regions of active fibrogenesis in the lung, are characterized by fibroblasts lacking the critical integrin adaptor protein, Thy-1. The loss of Thy-1 leads to aberrant mechanotransduction, myofibroblastic differentiation, and matrix remodeling. These changes are sufficient to recruit Thy-1 positive naïve fibroblasts into the fibrotic program and drive non-resolving fibrosis. The mechanism of Thy-1 loss in fibroblasts is not known. Separately, others have implicated inflammatory cytokines in the pathogenesis of pulmonary fibrosis without understanding how chronic inflammation leads to disrupted mechanotransduction and altered tissue mechanics driving disease progression. The objective of this application is to investigate the connections between inflammation and disrupted mechanotransduction characteristic of disease progression. I propose the central hypothesis that a novel IL-1-Thy-1 axis exists whereby IL-1 promotes acute Thy-1 loss in naïve fibroblasts and leads to a secondary wave of inflammation characterized by TNF-α production that results in chronic loss of Thy-1. We propose to identify the consequences of IL-1β- and TNF-α-mediated Thy-1 loss in lung fibroblasts by investigating myofibroblast differentiation and changes in mechanotransduction. Additionally, I will determine the mechanism of Thy-1 by looking at changes in vesicular shedding and epigenetic silencing using imaging flow cytometry and ATAC- Seq, respectively (Aim 1). Last, I propose to determine the localization and functional role of IL-1 and TNF-α in pulmonary fibrosis by using spatially targeted optical microproteomics and mouse models (Aim 2). This proposed work is significant in that it would fill a substantial gap in our knowledge by establishing a mechanism by which inflammation contributes to the onset and persistence of IPF through the establishment of stable fibroblast subpopulations. We pose an innovative hypothesis that seeks, for the first time, to bridge the gap between inflammation and disrupted mechanotransduction characteristic of disease progression.

特发性肺纤维化（IPF）是一种致命性疾病，没有明确的发病机制或治愈方法。其特点是 慢性炎症细胞浸润，炎症细胞因子升高，肌成纤维细胞积聚， 异常的细胞外基质（ECM）重塑。成纤维细胞灶，肺中纤维发生活跃的区域， 其特点是成纤维细胞缺乏关键的整合素接头蛋白 Thy-1。 Thy-1 的丢失导致 异常的机械转导、肌成纤维细胞分化和基质重塑。这些变化是 足以招募 Thy-1 阳性幼稚成纤维细胞进入纤维化程序并驱动非消退性纤维化。 成纤维细胞中 Thy-1 丢失的机制尚不清楚。另外，其他人也指出炎症 细胞因子在肺纤维化发病机制中的作用，但不了解慢性炎症如何导致 破坏机械传导并改变组织力学，导致疾病进展。此举的目的 应用是研究炎症和机械转导中断之间的联系 疾病进展的特征。我提出的中心假设是存在一种新的 IL-1-Thy-1 轴 IL-1 促进幼稚成纤维细胞中 Thy-1 的急性损失，并导致继发性炎症波 其特点是 TNF-α 的产生导致 Thy-1 的慢性丢失。我们建议确定 通过研究肌成纤维细胞来了解肺成纤维细胞中 IL-1β 和 TNF-α 介导的 Thy-1 丢失的后果 力转导的分化和变化。此外，我将通过以下方式确定 Thy-1 的机制： 使用成像流式细胞术和 ATAC 观察囊泡脱落和表观遗传沉默的变化 分别为 Seq（目标 1）。最后，我建议确定 IL-1 和 TNF-α 的定位和功能作用 通过使用空间靶向光学微蛋白质组学和小鼠模型来研究肺纤维化（目标 2）。这 拟议的工作意义重大，因为它将通过建立一种机制来填补我们知识上的巨大空白 炎症通过建立稳定的 IPF 来促进 IPF 的发生和持续 成纤维细胞亚群。我们提出了一个创新的假设，首次寻求弥合差距 炎症和疾病进展特征的机械转导破坏之间的关系。