The Inflammatory Bowel Diseases (IBD), including Crohn's disease and ulcerative colitis, remain one of the most debilitating inflammatory disorders of the western world. It is estimated that more than 1.5 million Americans suffer with IBD, with incidence rates on the rise in many populations. Among military veterans, IBD has one of the highest hospitalization rates of all diseases. Moreover, IBD-related cancer incidence is on the rise in some veteran populations. The precise etiology of IBD is not known. Inflammatory responses associated with IBD are characterized by precise molecular interactions between epithelial cells and leukocytes, including neutrophils, macrophages, and dendritic cells. Our ongoing studies have revealed that migrating neutrophils establish microenvironmental control of metabolism within inflammatory lesions. Under such conditions, epithelial cells have the capacity to dynamically control mucosal resolution and do so with a high degree of fidelity. It is only recently appreciated that inflammation-associated changes in metabolism are central to the inflammatory response. Indeed, the interactions of metabolism with the transcriptional and translational machinery significantly influence disease outcomes. The precise mechanisms by which metabolic pathways control resolution, however, have yet to be established. Work in progress has revealed that localized oxygen depletion (hypoxia) during inflammation significantly influences the metabolic demands of the tissue. In ongoing work, we have focused on defining how the transcription factor hypoxia-inducible factor (HIF) shapes the microenvironment of the inflammatory lesion. Using global chromatin immunoprecipitation promoter arrays (ChIP-chip) in conjunction with detailed NMR-based metabolomics, we have identified tractable HIF-specific targets in intestinal epithelial cells that control barrier function, particularly as they relate to rapid energy utilization (e.g. creatine kinase and the generation of phospho-creatine). In this proposal, we will define how epithelial metabolism molds the microenvironment during inflammation in the GI tract. Our project will place a particular emphasis on early events of the inflammatory response. Three synergistic specific aims are directed at testing the hypothesis that inflammation-associated changes within the microenvironment establishes metabolic control inflammatory resolution.
In Aim 1, we will define the functional implications of creatine metabolism in acute colonic inflammation.
Aim 2 will focus on the contribution of acute inflammatory cells to microenvironmental control of metabolic in vitro and in vivo.
Specific Aim 3 will elucidate the role of epithelial HIF-1 and HIF-2 specific metabolites and extend these findings to understand how such changes translate in chronic inflammation. It is our hope that these results will reveal new insights into innate regulation of mucosal inflammatory resolution and that extensions of this work will lead to targets for experimental therapeutics.
The Inflammatory Bowel Diseases (IBD), which include ulcerative colitis (UC) and Crohn's disease (CD), are diseases of the gastrointestinal tract that result from abnormal immune response in genetically-susceptible individuals. IBD has one of the highest hospitalization rates among military veterans (>100,000 hospitalizations from 1975-2006). Incidence rates of IBD are on the increase in some veteran populations and effective therapies are lacking in as many as 50% of patients. In addition, IBD-associated colon cancer is on the rise in some military populations. The proposed studies are designed to identify and harness information from novel inflammation-related metabolic pathways that promote tissue healing in representative models of human IBD. Results from these will provide new therapeutic options for patients with IBD.