Control of intestinal immunity by the autophagy protein ATG16L1 (360G-Wellcome-097112_Z_11_Z)

Autophagy is a process of recycling intracellular components in response to starvation or stress. It is also involved in clearance of defective organelles, intracellular pathogens and protein aggregates. Polymorphisms in autophagy genes were recently associated with susceptibility to inflammatory bowel disease (IBD); however the mechanisms responsible for this correlation remain unclear. Clinical and experimental evidence suggests that autophagy maycontribute to intestinal homeostasis in several ways, through distinct effects in intestinalepithelial cells and haematopoietic cells. The aim of this project is to test the hypothesis that autophagy contributes to intestinal homeostasis by influencing antigen presentation and inhibiting excessive proinflammatory responses in haematopoietic cells. Therefore, mice will be generated in which the autophagy pathway is selectively ablated in distinct haematopoietic cell lineages. Several complementary models of IBD will be employed to elucidate the functional consequences of autophagy defects in the context of intestinal inflammation. In parallel, in vitro approaches will be applied to characterize the impact of impaired autophagy on cellular physiology, bacterial handling and inflammatory responses in haematopoietic cells. Together, these experiments should identify mechanisms through which the autophagy pathway intersects withother immune pathways in the gut to regulate tissue protective and inflammatory responses.