The signaling role of alveolar type 1 cell-derived Wnt ligands during alveologenesis

1 型肺泡细胞衍生的 Wnt 配体在肺泡发生过程中的信号传导作用

• 批准号: 10063428
• 负责人: Odemaris Narvaez del Pilar
• 金额: $ 3.09万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063428
• 关键词: Affect; Alpha Cell; Alveolar; Animal Model; Area; B-Lymphocytes; Bronchopulmonary Dysplasia; Capillary Endothelial Cell; Cells; Chronic Disease; Data; Dimensions; Epithelial; Epithelial Cells; Epithelium; Fibroblasts; Functional disorder; Gases; Genes; Genetic; Genetic Transcription; Goals; Hyperoxia; Left; Ligands; Lung; Lung diseases; Mediating; Mediator of activation protein; Mesenchymal; Mesenchyme; Modeling; Morphology; Myofibroblast; Pathogenesis; Patients; Platelet-Derived Growth Factor; Population; Premature Infant; Proliferating; Pulmonary Fibrosis; Regulation; Research; Role; Signal Transduction; Source; Structure; Surface; Technology; Testing; VEGFA gene; WNT Signaling Pathway; WNT7A gene; beta catenin; cell type; conditional knockout; lung development; lung injury; mouse model; mutant; novel; single cell technology; single-cell RNA sequencing; surfactant

PROJECT SUMMARY Although surfactant producing alveolar type 2 cells have been the focus for many years, the alveolar type 1 (AT1) cells are the neighboring lung epithelial cells that cover >90% gas exchange surface area. We found AT1 cells are more than a passive structure because they express VEGFA and signal to the vasculature. We also found AT1 cells express Wnt ligands. Interestingly, cultured lung fibroblasts proliferate upon WNT3A stimulation and lung myofibroblasts express widely canonical Wnt target gene, Axin2. This led to our hypothesis that AT1 cells signal lung myofibroblasts via Wnt ligands. We will investigate the requirement of AT1-derived Wnt ligands for lung myofibroblasts during alveologenesis (aim 1), the epithelial-mesenchymal signaling mechanism (aim 2), and the Wnt-mediated crosstalk between AT1 and lung myofibroblasts in an experimental BPD models (aim 3). Successful completion of this study will reveal a new signaling role of AT1 cells and elucidate lung mesenchymal cell types, thereby representing a first step toward our long-term goal of unraveling epithelial-mesenchymal crosstalk during alveologenesis and BPD pathogenesis.

项目摘要 尽管产生表面活性剂的肺泡2型细胞多年来一直是焦点，但肺泡1型细胞仍是研究的重点。 (AT1)细胞是覆盖>90%气体交换表面积的相邻肺上皮细胞。我们发现 AT 1细胞不仅仅是一种被动结构，因为它们表达VEGFA并向血管系统发出信号。我们 还发现AT 1细胞表达Wnt配体。有趣的是，培养的肺成纤维细胞在WNT 3A 刺激和肺肌成纤维细胞表达广泛典型的Wnt靶基因Axin 2。这导致了我们的 假设AT 1细胞通过Wnt配体向肺肌成纤维细胞发出信号。我们将调查的要求 肺泡形成过程中肺肌成纤维细胞的AT 1衍生的Wnt配体（目的1），上皮-间充质 信号传导机制（目的2），以及Wnt介导的AT 1和肺肌成纤维细胞之间的串扰。 实验性BPD模型（目的3）。这项研究的成功完成将揭示AT 1的新信号作用 细胞和阐明肺间充质细胞类型，从而代表了朝着我们的长期目标迈出的第一步， 在肺泡形成和BPD发病过程中阐明上皮-间质串扰。