Cystic fibrosis (CF) is a disease characterized by defective Cl- ion transport, the accumulation and inability to clear away secretions, chronic bronchial infections, and increased mucus production. The increased mucus production and lung infections are major contributors to the morbidity and mortality of this disease. Prior analyses of mucus hypersection have been performed on complex mixtures of mucus obtained from an infected tissue. Results of these analyses have often been inconclusive. The recent development of probers for seven human mucins and five rodent mucins makes it possible to investigate the specific mucins involved in CF at a molecular level. The existence of animal models of CF have and will enable researchers to understand the mechanisms of the disease and design therapies to combat it. These models will be strengthened by our ability to express the human CF gene and the major mutations such as deltaF508 and G551D on the null mouse background. Our goal is to determine which specific mucins are over-produced in CF. Mucin expression in the gastrointestinal and reproductive tracts of the cf/cf mouse will be investigated as the CF mouse is a good model for intestinal disease. Human samples obtained from the Clinical Core will be utilized for respiratory tract analysis in addition to mouse tissues Expression of mucins and in particular, of the MUC1 mucin, will also be examined in mice expressing the human deltaF508 mutated gene and hCFTR on the cf/cf background. These mice will be generated by us in the Transgenic Core. A mucin that is widely expressed in epithelial tissues, Muc-1, appears to be up-regulated in the colon of the cf/cf mouse. Thus, we will mate our existing Muc-1 deficient mice with the cf/cf mice to determine the effect that a lack of Muc-1 mucin has on the CF phenotype.
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