BYPASSING THE SECRETORY DEFECT IN CYSTIC FIBROSIS

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DESCRIPTION (Adapted from applicant's abstract): The long-term goal is to develop information that may be useful in the understanding and treatment of cystic fibrosis, particularly with regard to its gastrointestinal manifestations such as meconium ileus. Cystic fibrosis is the most common, severe, autosomal recessive disorder among individuals of Caucasian origin. The disease is a disorder of epithelial transport, and results in significant morbidity and reduced life expectancy. Patients with cystic fibrosis have essentially absent cAMP-regulated chloride secretion in various tissues, including the airways, pancreatic and biliary systems, and the intestine. In the airways, there is an alternate pathway for chloride transport mediated by increases in intracellular calcium and a calcium-activated chloride channel (CaCC). However, both the cAMP and calcium-mediated pathways are defective in the intestines. The basis for the absent calcium-mediated secretion in the intestine is unknown, but may contribute significantly to the pathogenesis of gastrointestinal manifestations of the disease. In this regard, the investigators have shown that normal intestinal epithelial cells express agonist-sensitive, intrinsic negative regulatory signalling mechanisms that limit the expression of calcium-dependent chloride secretion. The investigators hypothesize that such mechanisms may also exist in the cystic fibrosis intestine, and that devising ways to circumvent these inhibitory signals may be of therapeutic benefit. The investigator will use a combination of complementary cell culture, electrophysiological, animal and molecular approaches to examine three specific aims. First, the investigator will determine whether there are fundamental differences in the expression of negative signalling pathways between airway and intestinal epithelial cells. Second, the investigators will determine whether such negative signals do in fact account for the failure of cystic fibrosis intestine to secrete chloride in response to calcium-dependent agonists. Third, the investigators will determine the molecular mechanism(s) whereby one key negative signal, inositol 3,4,5,6 tetrakisphosphate, exerts its inhibitory effects, and explore ways to circumvent this inhibition. In total, the studies should improve our understanding and the therapy of cystic fibrosis, both in general, and specifically with respect to the neonatal gastrointestinal manifestations that may have severe long-term health consequences.