Drosophila as a model to study modifiers of Cystic Fibrosis

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Summary/abstract Cystic Fibrosis (CF) is genetic disorder that effects approximately 30,000 people in the United states and more then 70,000 worldwide. CF is caused by mutations in the epithelial chloride channel CF transmembrane conductance regulator (CFTR) gene. In CF, loss-of-function mutations in CFTR, reduces chloride efflux from cells, and elevates the activity of the epithelial sodium channel (ENaC) through a mechanism that is not fully understood. This results in an increase sodium and water reabsorption, which ultimately leads to dehydration of the epithelial surface and reduction in mucus transport in multiple mucin-producing organs, such as the lungs, sinuses, intestine, pancreas, and reproductive organs. CF patients develop clinical symptoms in all these mucus- producing organs. In particular, most CF patients have shortened lifespans because of loss of CFTR in the respiratory tract, but also develop gut phenotypes early in the progression of the disease. These gut phenotypes are less studied than the lung phenotypes of CF but still significantly impact CF patients lives. While CF is caused by many different mutations in CFTR, the differences in CFTR function cannot explain the differences in patient symptoms. This indicates that many of the clinical phenotypes of CF are influenced by genetic modifiers and/or environmental factors. These genetic modifiers and environmental factors could be additional targets to develop treatments for CF that could be used to treat all patients regardless of the mutation they harbor. However, many of the potential genetic modifiers of CF are not well studied and the mechanism by which they modify CF phenotypes is unknown. Our lab has recently identified a Drosophila ortholog of the CFTR gene and established a CF model in the fly gut epithelium. In addition to observing CF phenotypes in the gut epithelium of CFTR mutant flies, we uncovered a micro RNA, mir263a, as a negative regulator of ENaC activity. Interestingly, the expression of mir263a is decreased in CFTR mutant flies, suggesting that that the regulation of ENAC by CFTR is regulated in part by mir263a. Here, I propose to further characterize the pathology of the fly mutant model including examining how bacteria can modulate disease phenotypes in this model. I will then use the fly CF model to gain new insight into ENaC, a known modifier of the CF phenotype. Finally, as the short lifespan, low cost, and genetic tractability of the fly makes it an ideal model organism to perform genetic screens, I propose to identify new potential genetic modifiers of CF. Altogether this work will establish Drosophila as a useful model to study CF and potentially provide new molecular targets for treatment of the disease.