早期生长反应因子Egr-1调控气道粘液蛋白MUC5AC的作用及机制研究

Mucus hyperscrection is the most risk factor for acute onset or exacerbation of chronic airway diseases, while the detailed molecular mechanisms underlying this reaction remain incompletely understood. We have recently observed that in human bronchial epithelial cells, the early growth response protein 1 (Egr-1) positively regulated the expression of MUC5AC induced by cigarette smoking extract or IL-13, and this effect might depend on the interaction of Egr-1 with another critical transcription factor AP-1. This project will further explore the role and mechanisms of Egr-1 in regulation of mucus hyperscrection in models of chronic airway diseases. In vitro we will utilize siRNA and cDNA to treat HBE cells or will isolate primary mouse tracheal epithelial cells from Egr-1 knockout mice to investigate the pivotal role of Egr-1 in mucus production, and to further study the underlying mechanisms. The Egr-1 knockout mice will also be used in disease models with mucus hyperscretion. This project aims to clarify the role and mechanisms of Egr-1 in regulation of MUC5AC expression, which should provide an experimental base and a new therapeutic target for mucus hypersecretion in chronic airway diseases.

气道粘液高分泌是多种慢性气道疾病急性发作并加重的常见原因，但其调控的分子机制尚未完全明确。我们最近的实验结果表明，在人体气道上皮细胞中，早期生长反应因子Egr-1能够调控香烟烟雾提取物或IL-13诱导的MUC5AC表达，其机制可能是通过与转录因子AP-1相互反应而实现对MUC5AC蛋白的转录调控。因此，本课题拟在此基础上进一步从体内体外模型明确Egr-1调控慢性气道炎症中粘液高分泌的作用和机制。体外研究拟利用siRNA或cDNA干预人体气道上皮细胞系或者提取Egr-1敲除小鼠原代气道上皮细胞，以阐明Egr-1对MUC5AC的关键调控作用并研究其具体分子机制；体内研究拟利用Egr-1敲除小鼠构建气道粘液高分泌相关模型来观察Egr-1在这些疾病模型中对粘液的调控作用。本课题旨在阐明气道上皮细胞中Egr-1调控MUC5AC的关键作用及机制，为气道粘液高分泌的治疗提供新靶点和重要实验依据。

气道粘液高分泌是多种慢性气道疾病急性发作并加重的常见原因，但其调控的分子机制尚未完全明确。本研究致力于探索早期生长反应因子Egr-1调控气道疾病中粘液蛋白MUC5AC的作用及机制。我们研究发现抑制Egr-1能够明显缓解香烟烟雾提取物（CSE）干预人气道上皮细胞（HBE）和IL-13干预Beas-2B 诱导的MUC5AC的分泌。进一步我们证明了该作用通过AP-1信号通路介导，AP-1介导Egr-1结合至MUC5AC的启动子引起粘液高分泌。我们还在体内体外实验中证明了通过NF-B和AP-1调控PM诱导的气道炎症和粘液，Egr-1对PM诱导的气道炎症和气道粘液具有正向调控作用，这个过程中PM中的多环芳香烃PAHs能够诱导Egr-1的表达，进而引起炎症反应和粘液产生。项目标注资助已发表负责人为通讯作者SCI论文1篇，另有1篇文章已被接收。我们的研究证明Egr-1在气道粘液高分泌中的具有重要作用，为临床治疗提供新的可能的治疗靶点。