Cystic fibrosis (CF) is due to defects in apical epithelial chloride channel, the cystic fibrosis transmembrane regulator (CFTR). CF can usually be traced with single point mutation in the CFTR which renders it incapable of transfer to the outer membrane. Although attempts at gene therapy have been unsuccessful, the artificial activation of calcium dependent chloride channels has promise. However, this is inhibited through two pathways. One, prolonged stimulation of phospholipase C (PLC) linked to elevated INS (3, 4, 5, 6) P4 levels; and two, growth factors TGFA and EGF elevate PIP 3 levels which also limits chloride secretion. We have identified compounds which reverse the effect of INS (3, 4, 5, 6), P4 and PIP 3. Either could be useful in the treatment of CF. To identify analogs which will be effective at lower concentrations, we will screen combinatorial libraries of Inositol polyphosphate analogs provided by Dr. Carsten Schultz. Moreover, calcium activated chloride channels and CF pancreatic epithelia are also inhibited by INS (3, 4, 5, 6), P4. Dr. Toan Nguyen will test whether this inhibition can be reversed in pancreatic epithelia. Finally, we will determine whether growth factors and PLC activators inhibit chloride secretion in airway epithelia and determine whether this can be reversed by our compounds.
The ultimate product will be an agent which alleviates symptoms of cystic fibrosis by augmenting chloride secretion through alternate pathways in mucosal epithelia. Such an agent may also be useful in the treatment of other respiratory illnesses.
|Moody, Mark; Pennington, Carey; Schultz, Carsten et al. (2005) Inositol polyphosphate derivative inhibits Na+ transport and improves fluid dynamics in cystic fibrosis airway epithelia. Am J Physiol Cell Physiol 289:C512-20|