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 2 a 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.
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