Inflammatory bowel disease (IBD) is a family of conditions characterized by chronic, relapsing inflammation of the gastrointestinal tract. IBD is especially prominent amongst military veteran populations, with one of the highest hospitalization rates of tracked diseases (>100,000 hospitalizations from 1975-2006) and accompanying high rates of hospital readmission. A recent study of the incidence of IBD in the veteran population has found that the incidence of IBD is 2-10 times greater than non-service members, showing a high degree of correlation with life stressors, and is on the increase in certain populations. Although treatments for IBD do exist, they are plagued by imperfections such as debilitating side effects (e.g., immunosuppression) and loss in effectiveness over time. Development of novel therapeutics is hampered by a poor understanding of the molecular mechanisms of IBD pathogenesis; consequently, a need exists to better understand the molecular pathophysiology of IBD to inform the development of novel therapies. One of the major molecular pathways associated with IBD is macroautophagy, hereafter referred to as autophagy. Autophagy is a conserved eukaryotic system wherein intracellular contents are recycled through the lysosome. Autophagy genes have been identified as IBD risk factors, and defects in autophagy have been experimentally shown to confer greater susceptibility to colitis in animal models. However, a complete understanding of the mechanism by which autophagy regulates IBD disease susceptibility is not known. Importantly, however, defects in autophagy appear to compromise normal host-microbe interactions at the intestinal interface by decreasing anti-microbial autophagy (“xenophagy”). Preliminary studies from our group have implicated autophagy in the proper function of intestinal epithelial cells (IECs). ChIP-chip analysis of hypoxia-treated IEC showed that several autophagy genes contained hypoxia-inducible factor (HIF) transcription factor binding sites in their promoter regions. HIF is a family of transcription factors responsible for the cellular response to low oxygen tensions and previously shown to be essential for intestinal homeostasis. These data also suggest that autophagy genes are transcribed preferentially by the HIF-1α isoform, as opposed to HIF-2α. In addition, hypoxia treatment of IECs increased autophagic flux in vitro, suggesting an increase in functional autophagy to hypoxia stimulation in addition to a transcriptional response. Finally, knockdown of HIF-1α increased susceptibility to the model intracellular bacterium Salmonella Typhimurium, suggesting a functional role for HIF in regulating xenophagy. Based on these and ongoing studies, we hypothesize that HIF-1α promotes xenophagy in the intestinal epithelium to regulate host-microbe interactions. To test this hypothesis, we propose three distinct but interrelated specific aims. We first propose to characterize epithelial HIF-dependency of autophag...