Progress towards understanding the etiology of Cystic Fibrosis as well as in detection and treatment has been substantial in the past few years. The use of DNA sequences closely linked to the CF locus enables prenatal diagnosis where there is a family history of the disease and lung transplantation is extending the life span of some patients. Clues about the nature of the anion permeability defect responsible for the pathological changes of epithelial tissues provide some hope that pharmacological therapies can be developed. The Hospital for Sick Children has a long term commitment to CF with a very large clinic and many ongoing research projects both basic and clinical. Some of these projects constitute a CF research Development Program directed primarily at the molecular cloning of the CF gene and its expression in sweat gland epithelial cell culture systems. The present application is intended to complement this program, to further integrate clinical and basic science studies and to exploit several strengths of this institution which are not included in the RDP. The central theme is the understanding of the basic defect in the different clinical phenotypes of the disease at the level of DNA haplotypes and ion transport mechanisms in the sweat gland, the lung and the pancreas. Hence the aims of the research project are; 1) The identification of a molecular alteration which underlies the apical chloride permeability defect. 2) The establishment of correlations between clinical and genetic variations in Cystic Fibrosis. 3) The use of optical imaging techniques to monitor CF ion transport defects. 4) The evaluation of the ion transport properties of alveolar epithelial cells of the lung in CF patients and normal subjects. 5) The examination of the role of the outwardly rectifying anion channel in pancreatic bicarbonate secretion 6) The comparison of the properties of this channel in nonepithelial cells with those in epithelial cells. Two core facilities will be required by these projects and will also greatly facilitate other CF projects which are already ongoing. First, the acquisition and culture of cells from the fetal lung alveolus and pancreatic duct will enable the cellular and molecular investigations to extend to these tissue. Second, the CF Biostatistics Core will provide ready access to clinical parameters of our large CF patient population and thus enable these to be correlated with properties such as DNA haplotypes and anion channel function.
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