REGULATION OF MUCIN GENE EXPRESSION BY ELASTASE

描述（根据应用改编）：中性粒细胞为主气道 炎症是慢性气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， 粘蛋白。这一行动很可能是一个关键环节， 炎症和粘液阻塞气道。目前，分子 弹性蛋白酶增加粘蛋白产生的机制是未知的。 三个初步的调查结果被引用后，一个假设的模型将是 测试：1）嗜中性粒细胞弹性蛋白酶增加编码两种蛋白质的mRNA的稳定性， 主要呼吸道粘蛋白、MUC 5AC和MUC 4; 2）中性粒细胞弹性蛋白酶 气道上皮细胞的治疗触发活性氧的产生 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的MUC 5AC和MUC 4 mRNA水平的增加。这 导致了以下假设。在呼吸道上皮细胞中性粒细胞 弹性蛋白酶处理通过以下途径增强MUC基因的mRNA稳定性 机制等神经弹性蛋白酶改变细胞氧化剂/抗氧化剂平衡 导致活性氧物质的产生。这些活性氧 物种，特别是过氧化氢和羟基自由基，介导 RNA结合蛋白和粘蛋白mRNA稳定序列之间的相互作用， 导致粘蛋白mRNA稳定性增加。强调必须 粘蛋白基因表达的翻译后调节，实验将测试 弹性蛋白酶调节粘蛋白mRNA的假设途径中的关键步骤 表情目的1研究弹性蛋白酶处理对相互作用的影响 RNA结合蛋白和粘蛋白mRNA稳定性序列之间的关系。Aim 2a研究 过氧化氢和羟基自由基对介导细胞凋亡的影响 弹性蛋白酶诱导的粘蛋白mRNA稳定性和粘蛋白mRNA水平的增加， Aim 2b研究了活性氧对分子间相互作用的影响。 RNA结合蛋白和粘蛋白mRNA的稳定序列，导致增加 mRNA稳定性和mRNA水平。最终目标是利用来自 该项目旨在确定治疗干预的新生物靶点， 预防慢性炎症性气道疾病中的粘液阻塞。

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.