REGULATION OF MUCIN GENE EXPRESSION BY ELASTASE

描述(改编自应用)：以中性粒细胞为主的呼吸道 炎症是慢性呼吸道疾病的主要病理特征。 中性粒细胞释放中性粒细胞弹性蛋白酶，刺激其增加 粘液。这一作用很可能是中性粒细胞 呼吸道发炎和粘液阻塞。目前，分子 弹性酶增加粘蛋白产生的机制尚不清楚。 引用了三个初步的发现，在此基础上将建立一个假设模型 测试：1)中性粒细胞弹性蛋白酶增加了编码两个 主要呼吸道粘蛋白、MUC5AC和MUC4；2)中性粒细胞弹性蛋白酶 呼吸道上皮细胞的治疗触发活性氧的产生 3)羟基自由基和过氧化氢清除剂抑制 中性粒细胞弹性蛋白酶诱导MUC5AC和MUC4基因表达增加。这 由此引出以下假设。呼吸道上皮细胞中性粒细胞 弹性酶处理通过以下途径增强MUC基因的mRNA稳定性 机械装置。中性粒细胞弹性蛋白酶改变细胞氧化/抗氧化平衡 导致了活性氧物种的产生。这些活性氧 物种，特别是过氧化氢和羟基自由基，介导了 RNA结合蛋白和粘蛋白mRNA稳定序列之间的相互作用， 从而提高了粘蛋白mRNA的稳定性。强调……的重要性 翻译后对粘蛋白基因表达的调控，实验将检验 弹性酶调节粘蛋白信使核糖核酸假说途径中的关键步骤 表情。目的1研究弹性酶处理对相互作用的影响。 RNA结合蛋白和粘蛋白mRNA稳定序列之间的关系。目标2a研究 过氧化氢和羟基自由基对细胞内脂质过氧化的影响 弹性酶诱导的粘蛋白mRNA稳定性和粘蛋白mRNA水平的增加，而 目的2b研究了不同活性氧物种对反应的影响。 RNA结合蛋白和粘蛋白mRNA稳定序列，导致增加 信使核糖核酸稳定性和信使核糖核酸水平。最终目标是使用来自 该项目旨在确定新的生物靶点，用于治疗干预 预防慢性炎症性呼吸道疾病的粘液阻塞。

DESCRIPTION (adapted from the application): Neutrophil-predominant airway inflammation is a major pathologic feature of chronic airway diseases. Neutrophils release neutrophil elastase that stimulates increased production of mucins. This action is likely to be a key link between neutrophilic inflammation and mucus obstruction of the airways. Presently, the molecular mechanisms by which elastase increases the production of mucins are unknown. Three preliminary findings are cited upon which a hypothetical model will be tested: 1) neutrophil elastase increases the stability of mRNAs coding for two major respiratory tracts mucins, MUC5AC and MUC4; 2) neutrophil elastase treatment of airway epithelial cells triggers generation of reactive oxygen species; and 3) hydroxyl radical and hydrogen peroxide scavengers inhibit neutrophil elastase-induced increases in MUC5AC and MUC4 mRNA levels. This leads to the following hypotheses. In respiratory epithelial cells neutrophil elastase treatment enhances mRNA stability of MUC genes via the following mechanisms. Neutrophil elastase alters the cellular oxidant/antioxidant balance resulting in the generation of reactive oxygen species. These reactive oxygen species, specifically hydrogen peroxide and hydroxyl radical, mediate the interaction between RNA-binding proteins and mucin mRNA stability sequences, resulting in increased mucin mRNA stability. Emphasizing the importance of post-translational regulation of mucin gene expression, experiments will test critical steps in the hypothetical pathway of elastase-reguated mucin mRNA expression. Aim 1 studies the effect of elastase treatment on the interaction between RNA-binding proteins and mucin mRNA stability sequences. Aim 2a studies the effect of hydrogen peroxide and hydroxyl radical on mediating the elastase-induced increase in mucin mRNA stability and mucin mRNA levels, while Aim 2b studies the effect of reactive oxygen species on the interaction between RNA-binding proteins and mucin mRNA stability sequences, leading to increased mRNA stability and mRNA levels. The ultimate goal is to use information from this project to identify new biologic targets for therapeutic interventions to prevent mucus obstruction in chronic inflammatory airway diseases.