Through study of the interaction between interferon beta (IFNbeta) and hypoxia-inducible factor 1 (HIF-1), important advances will be made in understanding epithelial regulation of the exposure of the immune system to contents of the intestinal lumen. It remains unclear how inflammation and hypoxia interact to influence the intestinal barrier in disease processes such as inflammatory bowel disease. The central hypothesis of this application is that hypoxia induces intestinal epithelial expression of INFbeta which functions in a feed-forward, autocrine manner to modulate HIF-1 expression and HIF-1 mediated responses to hypoxia, and this regulates the combined influence of hypoxia and inflammation on intestinal epithelial barrier function.
The specific aims of the proposed project are to: (i) define the expression and biology of IFNbeta in hypoxic intestinal epithelium, (ii) define the role of IFNbeta with respect to HIF-1alpha-mediated responses to hypoxia in intestinal epithelium, and (iii) define the role of IFNbeta on HIF-1 expression and resultant changes in barrier function. Additional work examines the in vitro effects of IFNbeta in models of hypoxia and inflammatory bowel disease to explore its role in disease. These studies will expand our knowledge of the actions of IFNbeta in the intestinal epithelium and our understanding of the regulation of epithelial barrier function.
