BIOCHEMISTRY OF CYSTIC FIBROSIS MUCOUS SECRETIONS

囊性纤维化（CF）是人类最常见的致死性遗传病

Cystic fibrosis (CF) is the most common lethal genetic disease in Caucasians. In CF, there is a hypersecretion of the respiratory mucus with altered physical properties which results in an impaired ability to clear the airways and thus causing a loss of normal protective function of the mucus secretions. These factors play an important role in the respiratory distress and progressive pulmonary involvement in CF. It is generally agreed that pulmonary involvement is responsible for most of the morbidity and mortality in CF patients. Recently, major advances have occurred in defining the genetics of CF and characterizing the basis biochemical defect in various epithelia with regard to electrolyte and fluid transport. Despite these advances, the molecular events leading to hypersecretion of mucus are not fully understood. We hypothesize that specific mucin genes are more highly expressed in CF. Since mucin glycoproteins (mucins) (secreted by surface goblet and submucosal gland cells) are the major macromolecular components of the mucus and are responsible for its viscoelastic and gel forming properties, alterations in mucins may affect the physiological behavior of mucus. There are least four human mucin genes expressed in airway epithelium; the relative expression of these genes is not known in CF and normal airway epithelium. Recently, our laboratory has identified and characterized a partial cDNA that encodes a major airway mucin which appears to be tissue specific (3). We have now further characterized this cDNA at the carboxyl end and have rigorously proved that the cDNA truly encodes a major airway mucin. The cDNA represents a portion of a novel mucin gene, which, tentatively, we have named MUC8. Both CF and normal airway tissues showed high level of expression of MUC8 which appears to be one of the major mucin messages in the airways. The long-term goal of our research is to elucidate the role of airway mucins in health and disease. The overall goal of this proposal is to characterize the gene for the novel major airway mucin MUC8 as well as study its regulation and expression. The specific aims of this application are: 1) to identify and characterize the full length cDNA encoding the major human airway mucin MUC8; 2) to determine the relative expression of airway mucin genes (MUC2, MUC4, MUC5 and MUC8) in CF and normal tracheobronchial tissue; 3) to detect the MUC8 transcript in mucus secreting cells using in situ hybridization; 4) to determine the organization of the MUC8 gene and identify regulatory elements that are involved in the MUC8 gene expression and 5) to investigate the influence of secretagogues on the regulation of MUC8 gene expression. The established tools and procedures of recombinant DNA technology and molecular biology will be applied to the understanding of MUC8 gene organization, regulation and expression in the airway epithelium. The knowledge gained from these studies would be essential in order to develop a rational approach to the treatment of CF which will ultimately require an ability to control the rate of mucus secretion and its viscosity.