The amount of fluid in the airways is determined by two processes; fluid secretion driven by Cl- transport from blood to lumen and fluid absorption following the reabsorption of Na+ from lumen to blood. In the fetus, secretory mechanisms predominate to produce fluid filled airways with the majority of the fluid absorbed at birth. In the adult, normal amounts of fluid are essential to mucus and ciliary movements. Disorders such as cystic fibrosis result from an imbalance in normal secretory processes caused by a reduction in Cl- secretion. This defect in C1- secretion is often compounded by an enhanced absorption of Na+. This proposal will focus specifically on the role of ion channels in transepithelial ion transport by human airways. Human fetal and adult trachea will be isolated from cadavers shortly postmortem and grown in tissue culture. The basic transport properties of the cultured cells including; short circuit current, transepithelial resistance and potential and the response to hormones will be measured to assess tracheal cell function in tissue culture. Na+ and Cl- channels will be studied using the patch clamp technique.
The aims are 1. to attain an understanding of the basic function of these channels, their role in airways fluid transport, and the exact pathways involved in their regulation, 2. to gain insights into the nature of ion channels in fetal trachea, their regulation and development and 3. to increase the understanding of the defect in the regulation of Cl- channels in cystic fibrosis. This research is consistent with the long range goals of the laboratory to identify, isolate, and understand the function of proteins involved in conductive movements of ions across epithelial cell membranes. The information obtained will aid in our understanding of normal adult tracheal function, the transition between fetal and adult, and the defect in cystic fibrosis.
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