The overall goal of this proposal is to test the hypothesis that the co- transporter, NKCC1, in parallel with CFTR and other apical membrane CL- transporters is required to regulate airway surface liquid volume in response to irritation and concomitant increase in mucin secretion by airway epithelium. The epithelia of the fetus is primary secretory. We believe that the movement of fluid across the fetal airway epithelium in both mouse and humans occurs by a variety of pathways, some of which involve the CFTR protein in parallel with the co-transporter. After birth, a decrease in the secretory function of airway epithelial cells must occur. This adjustment is brought about by decreasing the expression of the CFTR and NKCC1 genes and increasing the capacity of the airways to absorb Na+. It is perhaps only in the submucosal glands that the secretory function of the airway epithelium remains unchanged. We speculate that CFTR and NKCC1 co-transporter expression throughout the remainder of the adult airways reflects a preservation of the secretory ability of this airway. This secretory function may provide a sensitive inducible mechanism for adjusting the airway surface liquid volume. This may be mediated by increased secretion of fluid by epithelial cells of the small airways or by localized increases in secretion throughout the airways. The adjustment of the airway surface liquid volume by activation of Cl- secretion facilitates the flushing of noxious agents from the surface of the epithelium, and thus is critical for maintaining the health of the airways. To test this hypothesis we propose to generate mouse lines in which the function of the NKCC1 has been compromised. This mice will be generated from embryonic stem (ES) cell lines carrying a NKCC1 gene into which mutations have been introduced by homologous recombination. The impact of loss of this Cl-pathway on ion transport by airway epithelia and on the development and health of the mouse airways will be determined.
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