SCOR IN AIRWAY BIOLOGY & PATHOGENESIS OF CYSTIC FIBROSIS

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The goal of this SCOR is to understand the normal biology of airway epithelia and the pathogenesis of disease in cystic fibrosis (CF). The molecular defect in CF is the loss of CFTR Cl channel function, which results in defective transepithelial Cl transport. Recent studies that both normal and CF airway secrete substances with antibacterial activity in the airway surface fluid. Reports that CF surface fluid has a high NaCl concentration would explain the lack of bacterial killing in CF and tie the clinic defect to the molecular effect in the Cl channel. In Project 1, Drs. Welsh and Ostedgaard will focus on regulation of CFTR Cl channels by phosphorylation of the R domain. Phosphorylation is the physiologic mechanism that controls channel activity. Their studies should provide detailed functional and three-dimensional structural information about the R domain and new insights into the regulation of CFTR. In Project 4, Drs. Zabner and Smith will focus on regulation of airway surface fluid salt concentration by CFTR Cl channels. Complementary approaches will be used to measure human airway surface fluid salt concentration both in vitro and in vivo. Novel approaches to correct the abnormal composition of airway surface fluid will also be investigated. In Project 2, Drs. McCray and Tack will investigate the biology of human beta-defensins 1 and 2 (hBD-1 and -2). These salt-inhibited defensins are anti-microbial peptides expressed in airway epithelial. Their studies will determine the cell- specific localization, this diverse beta-defensin gene family. In Project 3, Dr. Engelhardt focuses on the integrated physiology of the airways. He will specifically examine the contribution of the sub-mucosal glands to airway defense mechanisms. This project uses a novel approach to the study of mouse and tracheal xenografts in the presence and absence of sub- mucosal glands. All of the projects depend on the Cell Culture Core for tissue acquisition and development of models relevant to CF airways. Insights gained from the comprehensive approach in this SCOR will improve our understanding of the pathogenesis of CF airway disease and may lead to novel therapies.