The Inflammatory Bowel Diseases (IBD), including Crohn's disease and ulcerative colitis, remain among 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. A recent study of more than 100,000 military service members estimated the incidence of IBD to be 2-10 times greater than non-service members, with a striking relationship between IBD incidence and the number of life stressors. The precise etiology of IBD is not known. Our interest is focused on the identification of inflammation-associated changes in tissue metabolsim during flares of IBD. These studies are founded on the observation that active intestinal inflammation in IBD is characterized by significant shifts in tissue metabolism that can influence cell and tissue function in fundamental ways. Under such conditions, epithelial cells have the capacity to dynamically control mucosal resolution and do so with a high degree of fidelity. The precise mechanisms by which metabolic pathways control resolution, however, have yet to be elucidated. Our 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 utilized global chromatin immunoprecipitation promoter arrays (ChIP-chip) in conjunction with detailed metabolomics to identify tractable metabolite targets in intestinal epithelial cells that control energy balance and barrier function. These studies have identified creatine and adenylate energy intermediates as checkpoint metabolites in epithelial barrier regulation during inflammation. In this proposal, we will define how epithelial metabolism molds the mucosal tissue environment during inflammation. Three synergistic specific aims are directed at testing the hypothesis that inflammation-associated changes within the tissue environment establishes metabolic control of inflammatory resolution through the promotion of mucosal barrier function.
In Aim 1 will focus on defining the role of adenylate energy metabolism and AMP kinase activation in barrier regulation within the mucosa.
Aim 2 will elucidate the function of creatine transport in the regulation of epithelial barrier function.
Specific Aim 3 will elucidate the role of creatine transport and adenylate energy metabolism in barrier regulation and wound healing in vivo. 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), including ulcerative colitis (UC) and Crohn's disease (CD), are diseases of the gastrointestinal tract that result from abnormal immune responses to luminal antigens in genetically-susceptible individuals. IBD represents a disease with among the highest hospitalization rates within military Veteran populations (>100,000 hospitalizations from 1975-2006) and incidence rates of IBD are on the increase in some populations. A recent study of more than 100,000 military service members estimated the incidence of IBD to be 2-10 times greater than non- service members, with a striking relationship between IBD incidence and the number of life stressors. The studies proposed here are designed to harness information from novel inflammation-related metabolic pathways that promote tissue healing in representative models of human IBD. It is our hope that results from these studies will provide new therapeutic options for military patients with IBD.
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