EGFR信号介导小气道基底干细胞分化在吸烟相关小气道重塑中的作用及机制研究

The human airway can be divided into 2 regions based on their diameters, the “proximal(big)” airways and “distal(small)” airways, which are covered by proximal airway epithelium and distal airway epithelium, and the distal airway epithelium is the initial and primary site for pathologic changes of smoking-relevant chronic obstructive pulmonary disease (COPD). In our previous study, we found that different regions had different structures and functional properties, which were determined and maintained by their different transcriptomes, but the distal transcriptome could be changed to proximal transcriptome by smoking. However, the mechanism of this "distal to proximal repatterning " was still unclear, which might be associated with EGFR signaling in distal airway epithelial basal stem cells. So we hypothesized that smoking-induced EGFR signaling shifts the differentiation fate of distal airway basal stem cells from the distal to proximal phenotype, which may be contribute to COPD and also could be reversed partially or totally by blocking EGFR signaling. To validate the hypothesis, we will investigate the effect of smoking on activation of EGFR signaling in distal airway in both vivo and vitro, and will confirm the regulation of EGFR signaling on distal airway basal stem cells through amplification and reduction of EGFR signaling. And to explore the effect of restoration of the unique biologic phenotype of the distal airway epithelium by modulating EGFR signaling in distal airway basal stem cells. Therefore, to provide a novel therapeutic approach for prevention and treatment of small airway disordering in smoking-relevant COPD.

人气道根据直径大小分为“大气道”和“小气道”，覆盖于相应气道上的上皮被称为大/小气道上皮，其中小气道上皮是吸烟相关慢性阻塞性肺疾病（COPD）病理改变发生的最早靶点。前期研究发现，大小气道上皮的特性由各自的转录组所维持，而吸烟及COPD可介导小气道中转录组朝着大气道改变，但介导了这一“小气道向大气道分化”病理重塑的具体机制不明，可能与表达于小气道基底干细胞的EGFR信号有关。故我们假设，吸烟通过增强小气道基底干细胞中的EGFR信号，介导其分化方向改变，发生COPD病理变化；而阻断EGFR信号，COPD小气道病理改变可部分/完全逆转。为验证假说，我们在体内外探讨人小气道上皮中，吸烟对EGFR信号的激活情况，通过功能获得缺失实验明确EGFR信号对小气道基底干细胞分化的调控作用，进而探讨阻断EGFR信号的靶向治疗对吸烟诱导人小气道上皮病理重塑的逆转作用，为防治吸烟相关COPD提供新的思路和靶点。

人气道根据直径大小分为“大气道”和“小气道”，覆盖于相应气道上的上皮称为大/小气道上皮，其中小气道上皮是吸烟相关慢性阻塞性疾病（COPD）病理改变的最早靶点。前期研究发现了大/小气道上皮的特性由各自的转录组所维持，而吸烟及COPD可介导小气道中转录组朝着大气道改变，但是具体机制不明。本研究验证了在中国汉族人群的大/小气道上皮中存在着各自的转录组，在吸烟后，小气道上皮转录组逐渐失去自己特性而获得部分大气道上皮转录组特性，且在吸烟相关COPD中表现更为明显。通过对健康者、健康吸烟者及COPD吸烟者的小气道上皮转录组分子通路分析后确立EGFR信号通路的作用较为显著，并通过建立体外模型进行验证。研究成功建立了人小气道上皮基底细胞体外培养、分化及吸烟造模模型，为进一步研究该类疾病的分子机制打下了良好的基础，并明确了EGFR信号对大气道上皮的维持作用，也明确了小气道上皮中EGFR信号被激活，可诱导小气道上皮朝着大气道上皮病理重塑。当重塑的小气道上皮中EGFR信号被不同程度阻断后，可部分逆转“小气道大气道化”的过程。研究阐明了中国人群的大/小气道上皮转录组特性和各自的特征性基因，明确了EGFR信号在吸烟及COPD相关小气道病理重塑中的调控作用，为防治吸烟相关COPD提供了新的治疗思路和潜在药物靶点。