Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

Cystic fibrosis is the most common autosomal recessive genetic disorder in Caucasians. The disease causes chronic bacterial infections, intestinal obstruction, pancreatic insufficiency and ultimately patients succumb to respiratory failure. Patients with cystic fibrosis are found to have an imbalance in fatty acids meaning arachidonic acid (omega-6) is elevated and docosahexaenoic acid (omega-3) is reduced. Our laboratory has found a defect in another class of lipids called ceramide. Ceramide is involved in the structure of the cell membrane, the inflammatory response and apoptosis. We have tested fenretinide as a treatment for cystic fibrosis since it was found in cancer studies to increase the levels of ceramide. We treated our mouse model of cystic fibrosis with fenretinide and observed a correction of ceramide levels. In addition, the fatty acid imbalance was corrected to reflect normal levels. Mice treated with fenretinide were able to fight off bacterial infections more efficiently than non-treated mice. This project continues to examine the effects of fenretinide in cystic fibrosis mainly by attempting to uncover the metabolic pathways which are affected by fenretinide. We will characterize the modifications of gene and protein expression induced by fenretinide. In addition, we will look at the enzymatic pathways of ceramide production to determine whether any modifications occur at this level. As a whole, this project will help elucidate the aberrant ceramide synthesis observed in cystic fibrosis, and the relationship between ceramide and fatty acids in the prevention of chronic infections.