Grant: Project Grant

Advances in treatment of Cystic Fibrosis (CF) has led to an increased life expectancy of CF patients. As more patients survive for longer, more of them are suffering from intestinal symptoms of the disease. These patients suffer from intestinal inflammation, obstruction and the overgrowth of intestinal bacteria but the mechanisms underlying these effects are not well understood. We analyzed the intestines of several mouse models for CF and found that CF mouse intestines were also inflamed. To understand better how the handling of intestinal bacteria may be altered in CF, we infected the CF mice with Citrobacter rodentium, a natural mouse pathogen that infects the intestinal tract and is widely used to study intestinal responses to bacteria. CF mice had striking defects in their handling of this bacterial infection, with uncontrolled growth of bacteria and defective immune responses, leading to high mortality. Further experiments unexpectedly showed that the cells lining the intestinal tract, which many have proposed are the cause of intestinal defects in CF, were not responsible for these effects. Investigating further we found that specific immune cells were altered in the CF mice, and we found defects in certain processes within these cells that could potentially explain the results. In this grant proposal we are proposing experiments that we anticipate will definitively identify the cell types responsible for the effects we see in the intestine in CF mice and in CF patients and will help us understand better the processes that are altered to cause these effects. Since there are already drugs available that target these processes, we will also test if these drugs can improve the defects we have described in the CF cells and mouse intestines. These studies would be a first step towards potentially repurposing these drugs to treat gastrointestinal symptoms of CF patients.