中性粒细胞胞外诱捕网（NETs）在慢性鼻窦炎（CRS）中诱导上皮-间质转化（EMT）的作用及机制研究

慢性鼻窦炎（CRS）是最常见的呼吸道疾病之一，造成巨大社会经济负担。最新研究发现中性粒细胞胞外诱捕网（NETs）在CRS中扮演重要角色，但机制不明。申请人前期研究发现：1）CRS患者鼻黏膜同时存在NETs和上皮-间质转化（EMT），且标志物水平呈正相关；2）测序提示NETs调控TGF-β通路；3）EMT相关通路中仅TGF-β1/Smad通路上调。据此，提出科学假设：NETs调控TGF-β1/Smad通路诱导鼻上皮发生EMT。本项目拟扩大样本量检测鼻黏膜NETs、EMT和TGF-β1/Smad通路水平，确认NETs与EMT及CRS疾病严重程度的关系；通过细胞分子实验明确CRS组织微环境诱导NETs形成，以及NETs诱导EMT发生的作用；通过调控TGF-β1/Smad通路活性，阐明NETs诱导鼻上皮发生EMT的分子机制。本课题有望为CRS的发病机制提供新的理论依据，以期发现新的生物学治疗靶点。

Chronic rhinosinusitis (CRS) is one of the most prevalent chronic respiratory diseases, which imposes immense socio-economic burden. Recent observations strongly suggest that neutrophilic extracellular traps (NETs) may play an important role in the pathogenesis of CRS. However, the pathogenic mechanisms remain largely unclear. In the preliminary experiments, we observed both NETs and epithelial-mesenchymal transition (EMT) in the nasal mucosa of CRS patients, and found a positive correlation between NETs and EMT markers. RNA-seq analysis of the clinical samples identified a potential relationship between NETs and TGF-β pathway in CRS patients. Moreover, the up-regulation of transforming growth factor-β1 (TGF-β1)-Smad signaling pathway was observed in the nasal mucosa of CRS patients, while no significant alteration was detected in other EMT-related pathways. Therefore, we postulate that NETs may induce EMT in CRS by targeting TGF-β1/Smad signaling pathway. In this study, the relationship between NETs and EMT levels, as well as that between NETs and the severity of CRS will be determined by detecting NETs, EMT markers, and TGF-β1/Smad pathway molecules in the nasal mucosa in a larger CRS cohort. In addition, in vitro functional experiments will be carried out to confirm the stimulation of NETs formation by the microenvironment of CRS tissues, and the induction of EMT by NETs. Finally, the mechanisms underlying the induction of EMT by NETs in nasal epithelium will be explored through modulation of the activity of TGF-β1/Smad pathway. This project may provide new insights into the pathogenesis of CRS and lead to novel therapeutic targets to ameliorate the disease.