The large surface area covered by the intestinal epithelium is particularly prone to inflammation-associated hypoxia as may occur during inflammatory bowel disease. Here, extracellular adenosine signaling events play a major role in attenuating acute inflammation, particularly during conditions of limited oxygen availability. However, extracellular adenosine has an extremely short half-life on the epithelial surface of the intestine. This is due to rapid transport by nucleoside transporters and enzymatic metabolism. Therefore, we hypothesized the existence of endogenous non-adenosine-like compounds with biological activity on adenosine receptors (ARs). To pursue this hypothesis, we screened fractions derived from supernatants of hypoxic epithelia for AR activity. These studies found a single fraction with biological activity. Using mass spectrometry, we found that this fraction contained a dominant peak consistent with the mass of the neuronal guidance molecule netrin-1. Such studies revealed a surprising role for neuronal guidance molecule netrin-1 in alternative adenosine receptor activation and attenuation of mucosal inflammation during hypoxia. Based on these preliminary studies, it is our hypothesis that endogenous netrin-1 is released from hypoxic epithelia, and attenuates inflammatory hypoxia through AR-dependent signaling pathways. In the present proposal, we will further characterize the role of netrin-1 in alternative AR activation and its biological role in endogenous attenuation of mucosal inflammation as occurs during experimental colitis.

Public Health Relevance

The present studies are designed to identify endogenous anti-inflammatory signaling pathways and to test these pathways in a therapeutic setting. This work will lay the groundwork for novel and specific therapeutic approaches in the treatment of mucosal inflammation, which are urgently needed - for example in the treatment of patients suffering from inflammatory bowel disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK083385-03
Application #
8278046
Study Section
Special Emphasis Panel (ZRG1-DKUS-C (02))
Program Officer
Hamilton, Frank A
Project Start
2010-05-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$282,871
Indirect Cost
$97,988
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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