Mucus hypersecretion is a major clinical symptom of cystic fibrosis, asthma, and COPD. A consequence is the formation of mucus plugs in small airways, which are sites of recurrent infection. These plugs also bring about oxygen insufficiency. The lethality of each of the above conditions is directly linked to the presence of excessive mucus. The substrate for hypersecretion is the pathological growth of airway mucus glands, which is reflected in increased gland:wall ratios consistently found at autopsy in these patients. The molecular mechanisms responsible for initiating gland growth in adult airways are unknown, but once understood, could open the way for drug development to help these patients. Based on our preliminary data and its similarity to findings in other systems, we propose that Mycoplasma elicits a convergence of stimuli at epithelial mesenchymal junctions leading to Lef-1/beta catenin overexpression and subsequent changes in gene expression in select epithelial cells. Among the genes so affected are E-cadherin and EMMPRIN. While downregulation of E-cadherin promotes bud formation by weakening adherens junctions, upregulation of EMMPRIN can be expected, based on our in vitro observations, to increase motility of the non-adherent cells.
In Aim 1, we will examine the dependence of gland bud formation on Lef-1, beta catenin, wnt and EMMPRIN, using selective siRNAs directed against each protein both in vitro and in vivo.
In Aim 2, we will test the hypothesis that Lef-1/beta catenin upregulation in gland buds is directly responsible for upregulation of EMMPRIN, whose promoter indeed contains putative Lef1-beta catenin response elements.
In Aim 3, we will identify the molecular changes in EMMPRIN-overexpressing epithelial cells contributing to the hypermotile phenotype. The results of the proposed studies should provide a molecular model of mucus gland formation in lung disease and suggest novel targets for the development of drugs to block hypersecretion and prolong life.
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