Is endoplasmic reticulum stress functionally involved in inflammatory bowel disease?

Inflammatory bowel diseases (IBD) are chronic relapsing intestinal inflammatory diseases. Intestinal barrier disruption is associated with increased apoptosis resulting in uncontrolled antigen influx and sustained inflammation. Recent genome-scans for IBD have highlighted the role of endoplasmic reticulum (ER) stress in IBD. Mutations in ER stress related genes have been associated with IBD and mice that lack a central regulator of ER stress (XBP1) develop spontaneous enteritis, associated with increased apoptosis of epithelial cells. To date, it is not clear whether the unfolded protein response (UPR) is beneficial or detrimental in IBD disease pathogenesis. We previously determined ER stress related gene expression signatures in biopsies that have been retrieved from patients with IBD. However, no information exists on the effect of manipulating the UPR in experimental models of gut inflammation. In the current proposal, we wish to determine 1) whether UPR signaling is activated early in the inflammation process or during recovery stages during DSS-induced colitis in mice; 2) whether manipulating the intestinal ER stress response in vivo is feasible; and 3) to determine if such interference can alter disease progression, allowing us to identify novel therapeutic agents.