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: 10166770
• 负责人: Daniel Abebayehu
• 金额: $ 6.83万
• 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/10166770
• 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）是一种致命疾病，没有明显的发病机理或治愈。它的特征是 慢性炎症细胞浸润，炎症细胞因子升高，肌纤维细胞积累和 异常细胞外基质（ECM）重塑。成纤维细胞灶，肺中活性纤维化的区域， 其特征是缺乏关键整合素衔接蛋白THY-1的成纤维细胞THY-1。 THY-1的损失导致 异常机械转导，肌纤维细胞分化和基质重塑。这些变化是 足以将THY-1阳性幼稚的成纤维细胞募集到纤维化程序中并驱动非分辨纤维化。 成纤维细胞中THY-1损失的机制尚不清楚。另外，其他人已经实施了炎症 细胞因子在肺纤维化的发病机理中，而不了解慢性炎症如何导致 机械转导和改变的组织力学驱动疾病进展的改变。这个目的 应用是调查注射和破坏机械转移之间的连接 疾病进展的特征。我提出了一个中心假设，即存在新型的IL-1-thy-1轴 IL-1在幼稚的成纤维细胞中促进急性THY-1损失，并导致炎症的继发波 以TNF-α产生为特征，导致THY-1的慢性丧失。我们建议确定 通过研究肌纤维细胞，IL-1β-和TNF-α介导的肺成纤维细胞中THY-1损失的后果 机械转移的分化和变化。此外，我将通过 通过成像流式细胞术和ATAC-查看囊泡脱落和表观遗传沉默的变化 SEQ分别（目标1）。最后，我建议确定IL-1和TNF-α的定位和功能作用 在肺纤维化中，通过使用空间靶向的光学微蛋白质组学和小鼠模型（AIM 2）。这 拟议的工作很重要，因为它可以通过建立机制来填补我们的知识的重大空白 通过建立稳定的注射促进IPF的发作和持久性 成纤维细胞亚群。我们提出了一个创新的假设，该假设首次寻求弥合差距 在炎症和疾病进展的机械转传特征之间的破坏之间。