Inflammation is accompanied by a substantial shift in tissue metabolism. One of the major metabolic signatures of inflammation is 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 recent years, we have focused on defining targets and molecular pathways set into motion by inflammatory hypoxia. Results from these studies have defined a series of novel signaling mechanisms in which hypoxia (both in vitro and in vivo) drives the metabolism of extracellular nucleotides toward the generation of large amounts of extracellular adenosine. Central to this pathway was the identification of hypoxia-inducible factor (HIF) as an important regulator of the enzymes necessary for Ado metabolism (esp. CD73), thus identifying HIF-regulated Ado production as an endogenous anti-inflammatory pathway. Ongoing studies have revealed that Ado regulates HIF through the active deneddylation of Cullins, a family of proteins critical for the recruitment of ubiquitin ligases. Based on these preliminary studies, we hypothesize that Ado generated early in the inflammatory response functions as a feed-forward anti- inflammatory mechanism through direct actions on mucosal HIF stabilization.
Three specific aims are directed at testing this hypothesis:
In Specific Aim 1, we will define the contribution of neutrophils and epithelia to Ado generation at sites of inflammation.
Specific Aim 2 will extend preliminary data to elucidate mechanisms of Ado-mediated Cullin-2 de-neddylation.
Specific Aim 3 will Probe the role of Ado to HIF-mediated protection. The overall aim of this proposal is to identify novel metabolic signaling by HIF and Ado within the mucosa during inflammatory hypoxia.

Public Health Relevance

This proposal aims at understanding the role of metabolism in mucosal inflammation such as that observed 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 these metabolic changes protective or detrimental to the tissue? 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK095491-02
Application #
8475473
Study Section
Special Emphasis Panel (ZRG1-DKUS-C (03))
Program Officer
Carrington, Jill L
Project Start
2012-06-01
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2013
Total Cost
$324,189
Indirect Cost
$114,301
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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Kelly, C J; Glover, L E; Campbell, E L et al. (2013) Fundamental role for HIF-1* in constitutive expression of human * defensin-1. Mucosal Immunol 6:1110-8

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