Mucins are high molecular weight glycoproteins which form a viscous gel lining epithelial surfaces forming a physical barrier between the host and the environment. All columnar epithelial cells secrete mucins, as do specialized goblet cells lining the gastrointestinal tract. A mechanistic understanding of mucin secretion has clinical relevance for a number of diseases including cystic fibrosis (CF), inflammatory bowel disease and peptic ulcer disease. Prior work on mucin secretion has been performed in neoplastic cells. Furthermore, much of the knowledge in this field is derived from the study of goblet cells. Whether the same processes apply to non-neoplastic columnar epithelial cells is not known. We propose to employ cystic fibrosis as a disease model to probe structural and functional aspects of mucin secretion in columnar epithelial cells. Thick mucus is a phenotypic hallmark and causes much of the morbidity of CF. Studies by our group and others show a complex relationship between CFTR, the chloride channel defective in CF patients, and the processes by which mucin glyproteins are secreted by columnar epithelial cells. We hypothesize that in CF columnar epithelial cells, post-translational processing of mucin glycoproteins and mucin granule exocytosis are altered.
The specific aims are to: 1. Characterize the signal transduction pathways involved in mucin secretion in columnar epithelial cells, and determine whether mucin secretion is dependent on chloride ion movements. 2. Investigate mucin post-translational processing in columnar epithelial cells. 3. Determine whether CFTR is functionally involved in mucous granule exocytosis in columnar epithelial cells. 4. Determine whether isolated mucous granules contain functional CFTR This proposal will provide a structured framework of research training for the candidate. The sponsor's group's expertise in biliary cell biology will ensure a supportive and stimulating environment for the candidate.
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