Epithelial stem cell hippo signaling in pulmonary fibrosis

肺纤维化中的上皮干细胞河马信号传导

• 批准号: 9919621
• 负责人: Stijn Piet Johan De Langhe
• 金额: $ 52.48万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-23 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9919621
• 关键词: AGTR2 gene; Age; Alveolar; Applications Grants; Architecture; Attenuated; Basal Cell; Bleomycin; Cartoons; Cell Density; Cell Differentiation process; Cell Lineage; Cell Maintenance; Cell physiology; Cells; Cessation of life; Characteristics; Chronic; Data; Development; Diagnosis; Disease; Epithelial; Epithelial Cells; Epithelium; Failure; Fibrosis; Gene Expression; Genetic; Goblet Cells; HIF1A gene; Histologic; Homeostasis; Impairment; Individual; Inflammation; Influenza; Injury; Interstitial Lung Diseases; Invaded; Lesion; Lung; Mediating; Mesenchymal; Modeling; Molecular; Monitor; Mus; Natural regeneration; Nuclear; Pathogenesis; Pathway interactions; Patients; Phosphotransferases; Pulmonary Fibrosis; Reporting; Resolution; Respiratory Failure; Role; Signal Transduction; Structure; Structure of parenchyma of lung; Structure of respiratory epithelium; Testing; Use of New Techniques; airway epithelium; airway remodeling; alveolar epithelium; beta catenin; bronchial epithelium; cell dedifferentiation; cell type; epithelial stem cell; epithelium regeneration; genome-wide; idiopathic pulmonary fibrosis; lung development; lung injury; notch protein; premature; pulmonary function; regenerative; repaired; response; role model; stem cells; tool; transcriptomics

Idiopathic pulmonary fibrosis (IPF) is a common form of interstitial lung disease (ILD) resulting in alveolar remodeling and progressive loss of pulmonary function, respiratory failure, and death often within 5 years of diagnosis. IPF pathogenesis encompasses fibrotic remodeling, inflammation, and loss of lung architecture. Although the underlying causes of the disease remain elusive, genetic and experimental evidence support the concept that chronic alveolar injury and failure to properly repair the respiratory epithelium are intrinsic to IPF disease pathogenesis. Histologically, respiratory epithelial cells in the lung parenchyma express atypical proximal airway epithelial and indeterminate cell type markers, including goblet and basal cell (BC) characteristics that are normally restricted to conducting airways. Fibrotic lesions and honeycomb structures replace alveolar structures, the latter normally lined by alveolar type 1 (AT1) and AT2 cells. Genome-wide transcriptomic analyses of lung tissue and isolated epithelial cells from IPF patients demonstrate dramatic changes in ciliated, basal, and goblet cell–associated gene expression and loss of normal alveolar epithelial cells, reflecting profound changes in epithelial cell differentiation and function in IPF. One strategy to attenuate or reverse the manifestations of IPF is to trigger proper alveolar regeneration by endogenous lung stem cells. Changes in cell density and matrix stiffness as a result of injury are sensed by the Hippo pathway, which controls stem cell quiescence. Recent reports also indicate increased YAP activity in respiratory epithelial cells in lungs of patients with IPF. Individual IPF epithelial cells that feature aberrant YAP activation in bronchiolized honeycomb regions frequently co-expressed AT1, AT2, conducting airway selective markers and even mesenchymal or EMT markers, demonstrating "indeterminate" states of differentiation not seen in normal lung development. Our preliminary findings indicate that inactivation of the Hippo pathway impairs alveolar epithelial regeneration, whereas inactivation of Yap promotes the resolution of pulmonary fibrosis. Using the new techniques and tools we have generated we will define the molecular pathways and mechanism by which the Hippo pathway controls alveolar epithelial regeneration after bleomycin injury.

特发性肺纤维化(IPF)是间质性肺疾病(ILD)的一种常见形式，可导致肺泡 肺功能重塑和进行性丧失，呼吸衰竭，通常在5年内死亡 诊断。IPF的发病机制包括纤维化重塑、炎症和肺结构丧失。 尽管这种疾病的根本原因仍然难以捉摸，但遗传和实验证据支持 慢性肺泡损伤和不能正确修复呼吸道上皮是IPF的固有概念 疾病发病机制。组织学上，肺实质中的呼吸道上皮细胞表达不典型 近端呼吸道上皮细胞和不确定细胞类型标记物，包括杯状和基底细胞(BC) 通常仅限于传导呼吸道的特征。纤维性病变和蜂窝结构 取代肺泡结构，后者通常由肺泡1型(AT1)和AT2细胞排列。全基因组 IPF患者肺组织和分离的上皮细胞的转录分析显示 正常肺泡上皮纤毛细胞、基底细胞和杯状细胞相关基因表达和丢失的变化 细胞，反映了IPF中上皮细胞分化和功能的深刻变化。一种减重策略 或逆转IPF的表现是通过内源性肺干细胞触发适当的肺泡再生。 由于损伤导致的细胞密度和基质硬度的变化是通过河马通路感受到的，这一通路 控制干细胞的静止状态。最近的报告还表明，呼吸道上皮细胞中YAP活性增加 在IPF患者的肺组织中。细支气管化的单个IPF上皮细胞具有异常的YAP活性 蜂窝区经常共表达AT1、AT2、传导气道选择性标志物，甚至 间质或EMT标志物，显示正常肺未见的“不确定”分化状态 发展。我们的初步发现表明，河马通路的失活损害了肺泡上皮细胞 而失活的YAP可促进肺纤维化的消退。使用新的 我们已经生成的技术和工具，我们将定义分子路径和机制，通过它 河马途径控制博莱霉素损伤后的肺泡上皮再生。