Inflammatory bowel disease (IBD) afflicts more than 1 million people in the United States. Although the pathogenesis of IBD is incompletely understood, clinical observations suggest a role for enteric bacteria. For example, some patients with IBD harbor an abnormal microbiota, both in terms of composition and ability to contact the epithelium. Given that the colonic epithelium is juxtaposed to the highest concentration of bacteria in the body (1012 organisms/gram), a precise understanding of the factor(s) that influence bacterial penetration through the adherent mucus is critical to the development of effective therapies. Epithelial secreted beta-defensin anti-microbial peptides are an important component of this barrier. These small, cysteine rich, cationic peptides are able to disrupt membrane integrity and kill of a wide range of microbes. Furthermore, defective expression of human beta-defensin 1 is associated with colonic inflammation in IBD. It is now appreciated that the colonic epithelium normally resides in a low pO2 (hypoxic) microenvironment and that hypoxia-inducible factor (HIF) transcription factors (HIF-1alpha and HIF-2alpha) that regulate hypoxia responses, are critical for normal colonic epithelial barrier function. Ongoing studies implicate HIF in the regulation of defensins. This project will test the hypothesis that HIF is a central regulator of beta-defensin expression in the intestinal epithelium. It is guided by three specific aims.
Aim 1 : Define the relationship between HIF signaling and beta-defensin expression in vitro.
Aim 2 : Characterize beta-defensin expression, its relation to HIF, and colitis phenotype in mice lacking epithelial HIF.
Aim 3 : Define the relationship between hypoxia and beta -defensin expression in the human colon. The long term objective of this project, in addition to characterizing beta-defensin expression, is to identify therapeutic targets for treatment of colitis and maintenance of disease remission. A comprehensive research training program has been developed that provides outstanding mentorship, resources, and environment. This includes a distinct mentorship team within the Mucosal Inflammation Program at the University of Colorado that will meet regularly and supplement mentorship provided by the applicant's thesis committee. All reagents, animals, access to human tissue, equipment, and space are available for completing each aspect of this project. Finally, a plan is in place to develop the research and academic skills of the applicant to provide training in all aspects necessary for a productive career as a physician scientist.