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）是一种致死性疾病，没有明确的发病机制或治愈方法。它的特点是 慢性炎性细胞浸润、炎性细胞因子升高、肌成纤维细胞蓄积，以及 异常的细胞外基质（ECM）重塑。成纤维细胞灶，肺中活跃纤维形成的区域， 其特征在于成纤维细胞缺乏关键的整合素衔接蛋白Thy-1。Thy-1的丢失导致 异常机械传导、肌纤维母细胞分化和基质重塑。这些变化是 足以将Thy-1阳性幼稚成纤维细胞招募到纤维化程序中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，其他人认为 细胞因子在肺纤维化发病机制中的作用，而不了解慢性炎症如何导致 破坏机械传导和改变组织力学驱动疾病进展。的目的 应用是研究炎症和破坏的机械传导之间的联系 疾病进展的特征。我提出了一个中心假设，即存在一个新的IL-1 β-Thy-1轴 由此IL-1 β促进幼稚成纤维细胞中Thy-1的急性丢失，并导致炎症的二次波 其特征在于导致Thy-1慢性丧失的TNF-α产生。我们建议确定 通过研究肌成纤维细胞，研究IL-1β和TNF-α介导的肺成纤维细胞Thy-1丢失的后果 分化和机械转导的变化。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， Seq，分别（目标1）。最后，本研究拟探讨IL-1 β和TNF-α在肝组织中的定位和功能作用 在肺纤维化中，通过使用空间靶向光学显微蛋白质组学和小鼠模型（目的2）。这 拟议的工作意义重大，因为它将通过建立一种机制， 炎症通过建立稳定的 成纤维细胞亚群。我们提出了一个创新的假设，第一次寻求弥合差距 炎症和疾病进展的机械传导特征被破坏之间的联系。