Mucosal inflammation is accompanied by substantial shifts in tissue metabolism. One of the major metabolic signatures of inflammation is tissue hypoxia, which is recently appreciated to significantly influence inflammatory disease outcome. Early in the disease process, such inflammatory hypoxia results, in large extent, from the recruitment of oxygen demanding inflammatory cell types, particularly neutrophils. In the past two years, we have made significant progress toward defining our original hypothesis that adenosine (Ado) generated early in the inflammatory response functions as a feed- forward anti-inflammatory mechanism through direct actions on mucosal hypoxia- inducible factor (HIF) stabilization. Utilizing new in vitro systems, novel murine models of inflammation and patient-derived materials, this work has revealed a number of important features related to mechanisms of anti-inflammatory Ado signaling. Ongoing work has defined a critical signaling axis wherein nucleotide metabolism is centrally coupled the HIF transcriptional network via cullin neddylation and the E3 ligase necessary for HIF stabilization. Likewise, this work has identified a previously unappreciated source of mucosal nucleotide released by activated PMN and provides a potentially rich source of Ado during active inflammation. Based on these preliminary studies, we hypothesize that nucleotides generated during acute inflammation directly impacts mucosal HIF stabilization and function.
Three specific aims are directed at testing this hypothesis:
In Specific Aim 1, we will elucidate mechanisms of nucleotide metabolism in the mucosa.
Specific Aim 2 will define the relative contribution of ecto-enzymes to Ado generation during mucosal inflammation.
Specific Aim 3 will examine the contribution of PMN-derived nucleotides on mucosal protection afforded by epithelial HIF. The overall aim of this proposal is to identify nove metabolic signaling by HIF and Ado within the mucosa during inflammatory hypoxia.
This proposal aims at understanding the role of adenosine metabolism in mucosal inflammation, such as occurs in inflammatory bowel disease (IBD). Results from the studies proposed here will go far to resolve a number of unanswered questions in the field of inflammation, including: What cell types contribute most significantly to the metabolic changes associated with inflammation? Are there novel metabolites produced during ongoing inflammation and are these metabolites protective or detrimental? Can these metabolic changes be targeted for therapeutic benefit? Answers to these questions through experiments proposed here will provide an important foundation for which to integrate novel therapeutic approaches for mucosal inflammation.
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