Epithelial ion transport is thought to be an important factor in disorders such as cystic fibrosis (CF), but the regulation of ion movement in vivo is not well understood. In CF, mutations in the chloride channel, CFTR, lead to increased sodium absorption across the respiratory mucosa, a process thought to contribute to the pathophysiology of the CF airway. If the increased absorption does contribute to the disease, it is not clear if it impacts on processes that allow bacterial infection to initiate, or if it aids in allowing the infection to persist, or both. Mechanisms implicating altered salt transport are controversial, but include l) reduced electrolyte levels leading to desiccated mucosa and poor clearance, 2) altering composition of the airway lining fluid in a way that lessens bactericidal activity of antimicrobial peptides, or 3) some other mechanism. Evidence also exists suggesting that the increased sodium absorption may not contribute to the pathophysiology, but is instead a consequence of signaling pathways altered in CF epithelia in response to the CFTR defect. To better understand the in vivo regulation of sodium transport and the role of CFTR in that regulation, this application proposes to map and identify genes contributing to natural variation in nasal transepithelial sodium transport by using inbred mouse lines C57)3L/6J and A/J and their hybrid progeny, recombinant inbred lines, and consomic lines. We have found that the inter-strain variation is quite heritable and is likely due to a small number of genes. To address the role of sodium transport m CF, murine CF alleles will be made congenic on inbred backgrounds associated with different levels of sodium absorption. The influence of sodium absorption on bacterially-mediated lung disease in these mice will be assessed using mice are induced to have a chronic infection by instilling bacteria-laden agar beads into the airway. The ability of the animals to clear the infection, as well as their inflammatory responses, will be monitored.
