Project 454891

Digestive tract disorders affect more than half of Canadians, who incur one of the highest prevalence of inflammatory bowel disease in the world. This fact argues that we need better treatments for digestive disease. Understanding how the intestine heals itself naturally will provide clues for new treatments, yet we are unable to watch the intestine's natural repair processes because they occur deep within our bodies. To address this problem, I have developed the fly gut as an experimental model: I feed flies a toxin and use microscopy techniques pioneered in our lab to watch the gut's protective lining - or brush border - degrade and then repair itself over 7-10 days. The fly intestine is relatively simple compared to the human intestine yet is similar in terms of cell composition and molecular regulation; thus, our studies in fruit flies will likely provide a template for similar studies in mammals. Here, I will use this new model to measure rates of brush border repair and identify how brush border repair is controlled by the gut's injury sensing signals. Our lab previously discovered a novel mechanism of brush border repair in which new replacement cells form their brush border in a protected compartment before merging seamlessly into the gut lining. However, much about how this repair process works remains unknown. By taking snapshots of the gut inside living flies at different times, I will map the formation of the new brush border from start to finish and identify where its particular 'building blocks' are incorporated. I will also examine how the gut's injury response signals act on these 'building blocks' during the repair process. Identifying the cellular mechanisms of brush border damage and regeneration will provide fundamental insights into mechanisms of epithelial repair and may lead to therapeutic applications to mitigate damage from gastrointestinal disorders in humans.