Therapeutic Potential of Targeted Mucosal Heme Oxygenase-1 in Colitis

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Disruptions in the complex balance between inflammatory and homeostatic signaling in the intestinal mucosa can result in diseases such as inflammatory bowel disease (IBD). From this perspective, there is significant interest in identifying endogenous homeostatic pathways in the intestinal mucosa. Targeted activation of these mucosal pathways may restore homeostasis and at the same time avoid the risks of systemic immunosuppression which is frequently utilized for control of IBD. Heme oxygenase-1 (HO-1) and its metabolic by-product carbon monoxide are activated in the setting of oxidative stress. Stimulation of this pathway has been demonstrated to be protective in several murine models of IBD. Activation of the HO-1 pathway in macrophages has been shown to augment bacterial killing and negatively regulate proinflammatory cytokine expression in the intestinal mucosa. We have also identified an anti-inflammatory role for intestinal epithelial HO-1. Hypoxia inducible factor (HIF) is a transcription factor that is activated in the setting of hypoxic stress. Stabilization of epithelial HIF is protective against intestinal inflammation. It is a transcriptional activator of HO- 1 but a relationship between the protective impact of HIF and HO-1 in chronic intestinal inflammation has not previously been established, nor has the regulatory relationship between the two been examined in intestinal epithelial cells or macrophages. The proposed project will test the hypothesis that stabilization of HIF in intestinal epithelial cells and MΦ is protective against intestinal inflammation through induction of HO-1. Based on our preliminary data, this is pursued with the following objectives: 1. Define the contribution of HO-1 to the protective impact of epithelial HIF in mucosal inflammation. 2. Determine if myeloid HIF is protective against intestinal inflammation through HO-1. 3. Test the efficacy of selective induction of HIF/HO-1 for amelioration of chronic intestinal inflammation. This proposed project is part of a plan to support the Candidate's career development into an independently funded, VA-based, physician-scientist through an appropriately structured combination of research, training and mentoring activities. The Candidate is a gastroenterologist with a focus on IBD and homeostatic pathways of the mucosal immune system. With the support of this award, a nationally recognized research institution, and experienced mentors, this project will advance expertise in integrated mucosal biology and proficiency in therapeutic modulation of mucosal anti-inflammatory pathways for treatment of IBD.