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 M? 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.
Inflammatory bowel disease has one of the highest hospitalization rates among veterans (>100,000 hospitalizations from 1975-2006). Current therapies primarily involve systemic immune suppression. This carries certain risks, including an increased risk of infection and malignancy. The risks are more significant with increasing age, duration of use and in patients who require a combination of drugs for disease control. Additionally, many patients do not respond to available therapies and the costs of many options are significant. The veteran population includes a substantial proportion of older patients susceptible to these risks, as well as young patients who may have to be on these medications long term. To address these problems, novel and safer therapeutic strategies are needed. This project is designed to evaluate the therapeutic potential of targeted activation of two important homeostatic pathways using novel approaches that can be harnessed to characterize and translate the potential of other mucosal homeostatic pathways.