Receptor-mediated Control of Pulmonary Ionocytes

PROJECT SUMMARY/ABSTRACT Maintaining the appropriate volume of airway surface liquid is crucial for respiratory health. Airway epithelia control airway surface liquid volume by balancing the absorption and secretion of liquid. Recent studies re- vealed that ionocytes perform most of the salt and liquid absorption, and secretory cells perform most of the secretion. Both cell types use cystic fibrosis transmembrane conductance regulator (CFTR) channels to control Cl– movement across the apical membrane. This raises the question—how do airway epithelia balance the contributions of two neighboring cell types that perform opposing functions through the same apical channel? The long-term goal is to establish new regulatory nodes between ion transport, its regulation, and physiological function and then target these mechanisms in pulmonary diseases. The overall objective of this application is to define the mechanism by which PGE2 balances absorption and secretion to target novel mechanisms that control airway surface liquid volume. The central hypothesis is that PGE2 production balances ASL absorption and secretion by regulating ionocytes and secretory cells simultaneously. The central hypothesis will be tested by pursuing the following specific aims posed as questions: 1) How does PGE2 balance airway epithelial Cl– absorption and secretion? 2) How does PGE2 modify the ASL? The proposed research is innovative because it tests the hypothesis that PGE2 turns off CFTR in ionocytes while turning on CFTR in secretory cells. The mechanism is the first example of how one molecule can control CFTR in two neighboring cells performing op- posing functions. The proposed research is significant because results identify new targets for therapeutic in- terventions in pulmonary diseases.