miR-146a介导自噬调控慢性鼻-鼻窦炎中MUC5AC表达的作用及机制研究

Chronic rhinosinusitis(CRS) is a disease with mucus hypersecretion of nasal navity and sinus , the main ingredient of mucus is MUC5AC,which is over-expresed in CRS,however,its mechinism of regulation is unknown.It was reported that human neutrophil elastase（HNE）can induce cell autophagy,which is required for MUC5AC expression,meanwhile,MiR-146a can negatively regulate HNE-induced MUC5AC secretion.Our previous research demonstrated that human neutrophil elastase（HNE）is an important factor of MUC5AC over-expression.In our primary experiment,the expression of autophage related proteinLC3B-Ⅱwas higher and expression of MiR-146a was lower in CRS patients than normal one. Taken together, we hypothesize that miR-146a can negatively regulates neutrophil elastase-induced MUC5AC secretion by autophagy. In our study,we will detect the expression of miR-146a、LC3B-Ⅱ in CRS with more samples,then establish the primary nasal epithelium cells and high mucus rats models and detect the role and mechanism of miR-146a to the MUC5AC expression induced by HNE through autophagy. The aim of our study is to illuminate the role and mechinism of regulation to increase MUC5AC secretion in CRS and supply the theoretical reference for immunotherapy to cure CRS patients.

慢性鼻-鼻窦炎（CRS）是黏液高分泌性疾病，表现为黏液主要成份黏蛋白MUC5AC过度表达，但调控MU5AC表达的机理还不清楚。文献报道人嗜中性粒细胞弹性蛋白酶（HNE）能诱发自噬的发生，自噬参与MUC5AC的过度表达，miR-146a能负调控HNE引起的MUC5AC表达。我们前期研究发现HNE是CRS中MUC5AC的重要诱发因素，初步实验结果显示CRS中自噬相关蛋白LC3B-Ⅱ表达升高，miR-146a表达下调。据此，我们假设在CRS中miR-146a介导自噬负调控HNE所致的MUC5AC过表达。为此，本研究拟扩大样本检测CRS中miR-146a、LC3B-Ⅱ等的表达情况；通过体外鼻黏膜原代细胞培养和小鼠鼻腔黏液高分泌模型，检测自噬对HNE诱导MUC5AC表达的影响及miR-146a在其中的调控作用。本课题的实施旨在于阐明CRS中MUC5AC表达的调控机制，为CRS的免疫治疗提供理论依据。

慢性鼻-鼻窦炎（CRS）是黏液高分泌性疾病，表现为黏液主要成份黏蛋白MUC5AC过度表达，但调控MU5AC表达的机理还不清楚。文献报道人嗜中性粒细胞弹性蛋白酶（HNE）能诱发自噬的发生，自噬参与MUC5AC的过度表达，miR-146a能负调控HNE引起的MUC5AC表达。我们前期研究发现HNE是CRS中MUC5AC的重要诱发因素，初步实验结果显示CRS中自噬相关蛋白LC3B-Ⅱ表达升高，miR-146a表达下调。据此，我们假设在CRS中miR-146a介导自噬负调控HNE所致的MUC5AC过表达。为此，本研究拟扩大样本检测CRS中miR-146a、LC3B-Ⅱ等的表达情况；通过体外鼻黏膜原代细胞培养和小鼠鼻腔黏液高分泌模型，检测自噬对HNE诱导MUC5AC表达的影响及miR-146a在其中的调控作用。该研究的结果提示：miR-146a可通过抑制EGFR的磷酸化来降低MUC5AC的表达水平，EGFR是miR-146a的靶基因；在CRS 中HNE 促进自噬的发生，从而激活JNK-AP-1 通路而导致MUC5AC过度表达。本课题的实施旨在于阐明CRS中MUC5AC表达的调控机制，为CRS的免疫治疗提供理论依据。