Mechanisms of intestinal epithelial responses to inflammatory modulators

Inflammatory bowel diseases (IBD) are on the rise in the western world, and colon cancer is a leading cause of cancer-related deaths worldwide. Both these diseases involve the intestinal epithelium, the single layer of epithelial cells that is responsible for nutrient absorption and also for protection from the external environment. Associated with the gut epithelium is a complex network of immune cells that help to protect the epithelium against environmental insults. The continuous exposure to food-derived particles, innocuous microbial products from commensal bacteria, as well as pathogenic bacteria, viruses and fungi, require the gut immune system to maintain a fine balance between non-responsiveness and full activation and inflammation. Understanding how the epithelium responds to inflammation is of paramount importance to understand how the epithelium contributes to resolution of inflammation. Furthermore, knowing the mechanisms that contribute to defects in this balance as occurs in IBD is key to detect and treat these common diseases. Using intestinal epithelial organoids our work aims to determine the molecular detail that underpin responses of the epithelium to different inflammatory mediators, specifically how they affect proliferation, differentiation, gene expression, and barrier function. Furthermore, we will identify signalling pathways involved and measure the contributions of novel immune response modulators including the aryl hydrocarbon receptor (AHR) and Hypoxia-inducible factor 1 (HIF1alpha). This will establish how inflammatory responses in the gut are coordinated. Finally, we aim to create a pilot repository of intestinal organoids derived from genetically modified mice that will serve as an experimental resource for animal replacement within the scientific community.