Tissue metabolism in ongoing inflammatory responses is an area of significant interest. Within the mucosa, changes in metabolism are associated with shifts in availability of O2 and the expression of O2-sensitive genes, particularly those regulated by the transcription factor hypoxia-inducible factor (HIF). As work in progress, we have focused on understanding molecular pathways and functional endpoints initiated by the stabilization of intestinal epithelial cell (IEC) HIF. These studies have revealed that diminished O2 availability (hypoxia) is a major contributing factor to the resolution of intestinal inflammation. Studies from cultured cell systems, animal models and human tissues have revealed that metabolites generated within the inflammatory microenvironment are central to barrier regulation and anti-microbial function. Results from animal models of intestinal inflammation have demonstrated an almost uniformly beneficial influence of HIF-1 stabilization on disease outcomes, particularly related to the resolution of mucosal inflammation. Nonetheless, we believe that there is significant untapped potential within this field of study. We hypothesize that HIF-1 and HIF-2- dependent signaling evokes a pro-resolving epithelial phenotype during intestinal inflammation. Three synergistic specific aims are proposed. In Aim 1, we will distinguish the select regulation of epithelial junctional proteins by HIF-1 and HIF-2. Aim 2 will develop and test a new class of HIF prolyl hydroxylase inhibitors (PHDi) on mucosal barrier function and wound healing. Specific Aim 3 will evaluate in vivo endpoints of pharmacological HIF stabilization. Results from these experiments will provide new insights into innate regulation of mucosal barrier and an expanded role for PHDi in the resolution of mucosal inflammation. It is our hope that extensions of this will lead to the identification of new therapeutic targets for mucosal inflammatory disease.