MUC 2 GENE ACTIVATION IN DEVELOPMENT AND DISEASE

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Chronic obstructive airway diseases such as cystic fibrosis are characterized by mucin overproduction. Over time, this can lead to the formation of mucus plugs, infection, bronchiectasis, respiratory insufficiency, and death. An understanding of how this sequence of events is triggered would help in the design of methods to inhibit it. During the last period, our experiments confirmed the hypothesis that an early event in experimentally induced hypersecretion is the upregulation of steady state mucin (MUC 2) mRNA (induced by endotoxin instillation in rat airways). Our experiments also revealed a phasic upregulation of MUC 2 early in tracheal development. The goal of the proposed studies is to gain information about how these events are triggered and controlled. Studies listed under Specific Aim l will determine, using in situ hybridization, the time course of MUC 2 activation in the developing trachea. In addition, they will identify relevant protein-DNA interactions by gel shift and footprinting assays, isolate footprinted proteins and map the time and place of their expression during development. They will also attempt to identify genes controlling the mucous cell phenotype as a whole and identify mesenchymal induction factors activating their expression. Studies listed under Specific Aim 2 will determine, using epithelial cell cultures, whether the endotoxin upregulation of MUC 2 previously observed in vivo is a direct effect or is mediated by neutrophil products. Other studies will determine the extent to which mucin induction by endotoxin is transcriptional or post-transcriptional and identify protein-DNA interactions mediating this induction. Because recent experiments have revealed MUC 2 upregulation by Pseudomonas (PA) products, additional studies will analyze the PA-MUC 2 induction by methods similar to those used to analyze the endotoxin-MUC 2 induction and attempt to identify the active component in PA supernatant. The information gained from these studies will hopefully suggest pharmacological interventions to inhibit excessive mucin production in human airways.