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: 10541057
• 负责人: Stijn Piet Johan De Langhe
• 金额: $ 35.07万
• 依托单位: MAYO CLINIC ROCHESTER
• 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 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10541057
• 关键词: Epithelial; stem; cell; hippo; signaling

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fipfrosis（IPF）是实习生肺疾病（ILD）的一种常见形式，导致肺泡 经常在5年内的5年内，经常在5年内进行肺功能，呼吸衰竭和死亡的重塑和逐步丧失 诊断。 Allooth疾病的根本原因仍然难以捉摸，遗传和实验支持 慢性肺泡损伤和无法正确呼吸上皮的概念是固有的 疾病发病机理。 近端气道上皮静脉细胞类型标记，包含的goveblet和基底细胞（BC） 通常仅限于进行气道的特征。 代替牙槽结构，后者通常用牙槽1（AT1）和AT2细胞衬里 来自IPF患者的肺组织和分离的癫痫发作细胞的转录组分析表现出戏剧性的 正常肺泡上皮的纤毛，基底和goveblet细胞相关基因表达的变化 细胞，反映了上皮细胞细胞细胞差异的深刻变化，而在IPF中的功能。 或逆转IPF IPF的表现是通过内源性肺干细胞触发适当的肺泡再生。 细胞密度的变化和矩阵刚度作为结果的变化是通过河马途径感知的，河马途径是 控制干细胞的静止。 IPF患者的肺部。 蜂窝区域经常共表达AT1，AT2，进行气道选择性标记，甚至 间充质或EMT标记，表明在正常肺中未见的“不确定”状态 开发。 再生，而YAP的灭活促进了肺纤维化的分辨率。 技术和工具我们将定义您的分子途径和机制 河马途径控制博来霉素损伤后肺泡上皮化。