BRONCHIAL SECRETIONS--PHYSICAL AND CHEMICAL STUDIES

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Mucin glycoproteins (mucins), the major components of the mucosal layer that protects and lubricates mammalian airways, are secreted by epithelial cells lining the lumen and submucosal glands. These cells and glands exhibit hyperplasia in chronic obstructive pulmonary diseases. Little is known about the mechanism or factors initiating or regulating metaplasia and hyperplasia, although it has recently been proposed that initiation of transcription of mucin protein genes by serous cells in rat airways is a primary event leading to goblet and mucous cell metaplasia and hypersecretion (1). Current evidence indicates that several mucin genes are expressed both in the airways and intestine. We speculate that the specific mucin proteins are more highly expressed in airway diseases (perhaps by specific airway cells) and that different members of the airway mucin protein gene family provide unique substrates for specific glycosyltransferases. The long term objective of our research program is to elucidate the role of airway mucins in health and in diseases. We have recently identified and characterized a cDNA clone that encodes TBM, a human tracheobronchial mucin that appears to be airway-specific. The specific aims of this proposal are: [1] To identify and characterize full length cDNA clones encoding TBM and to delineate similarities and differences to other mucins as such information becomes available. [2] To elucidate the cell and tissue specificity of mucin genes by in situ hybridization and Northern blot analysis and determine whether the expression of specific mucin genes is affected in airway diseases. [3] To isolate and characterize genomic DNA for TBM. The cDNA clone that encodes for TBM will be used to probe genomic libraries. TBM genomic clones will be characterized by chromosomal location, restriction mapping, S1 mapping, and by sequence analysis of the exon/intron boundaries. [4] To investigate expression and regulation of the TBM gene. We will determine the transcriptional activity of the TBM gene. Should it prove transcriptionally active, the promoter sequences of the genomic clones identified in aim [3] will be studied for regulatory elements using promoter deletion constructs.