The airway mucus layer coats the epithelium, provides a protective barrier against infectious agents, and participates in the mucosal response to inflammation and infection. The physiochemical and biological properties of mucus are largely conferred by mucins glycoproteins (mucins) - large, highly O-glycosylated, sticky, viscoelastic macromolecules. Mucins are hypersecreted in response to infection and inflammation and obstruct the airway in chronic obstructive pulmonary diseases. Mucin hypersecretion implies upregulation of MUC genes. Seven of the nine MUC genes identified to date are expressed in respiratory tract tissues and cells and MUC4, MUC5, MUC5B, and MUC8 genes appear to be well-expressed normally while expression of the secretory mucin genes MUC2 and MUC5 appear to be altered by infection and in airway diseases, at least in cystic fibrosis. Dr. Rose's long term objective is to elucidate the role of secretory mucins encoded by the MUC5 gene in airway health and diseases. MUC5, which normally exhibits tissue and cell-specificity, seems to be differentially expressed in airway diseases. The overall hypothesis is that regulation of the MUC5 gene and expression of MUC5 mucins impact on the pathogenesis of chronic obstructive pulmonary diseases. To address this hypothesis, Dr. Rose will [1] compare the characterization of the transcriptional unit of the MUC5 gene; [2] characterize the airway cell specificity and interleukin-responsive elements of the MUC5 promoter; [3] determine whether MUC5 is regulated in vitro by specific inflammatory mediators and whether MUC5 expression and MUC5 mucin production are altered in obstructive pulmonary diseases; [4] initiate structure/function of MUC5 mucins. An understanding of MUC5 gene regulation and of the structure/function characteristics of the MUC5 gene products may ultimately provide strategies to prevent mucin hypersecretion and circumvent mucus obstruction in obstructive pulmonary diseases.
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