Mucosal organs such as the intestine are highly vascular organs with extensive metabolic demands. Epithelial cells which line the intestine function to orchestrate a multitude of mucosal responses, and given their anatomic location, are primary targets for diminished blood flow and resultant tissue hypoxia. Our previous studies have explored the response of intestinal epithelial cells to hypoxia and these studies defined a transcriptional signaling pathway mediated by hypoxia-inducible factor (HIF). Activation of HIF results in the coordinated induction of a cluster of apically-localized, barrier protective gene products. Such induction parallels the accumulation of polymorphonuclear leukocytes (PMN, neutrophils). In this proposal, we will test the hypothesis that HIF coordinates protective epithelial responses to hypoxia.
Three specific aims are proposed to test this hypothesis. First, we will elucidate the role of PMN to """"""""inflammatory hypoxia"""""""" using in vitro and in vivo models of intestinal inflammation. Second, we will build on recent findings to further explore the role of HIF signaling to intestinal inflammation. In particular, we will define the contribution of HIF-1 and HIF-2 to protection afforded by inflammatory hypoxia. Third, we will extend our recent findings with pharmacological approaches that activate HIF (prolyl-hydroxylase inhibitors) to define specific targets and mechanisms of protection in both chemically- and genetically-induced murine models of intestinal inflammation. The overall aim of this proposal is to elucidate the how hypoxia and inflammation coordinately influence disease outcomes at the mucosal interface.

Public Health Relevance

These studies are proposed to better understand basic mechanisms of inflammation in the intestine. Specifically, these studies will define how metabolic shifts present during episodes of inflammation might be harnessed to develop novel therapies for mucosal diseases. It is our hope that extensions of this work in human patients might impact inflammatory disease outcomes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK050189-20
Application #
8514579
Study Section
Special Emphasis Panel (ZRG1-DKUS-C (03))
Program Officer
Carrington, Jill L
Project Start
1995-09-25
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
20
Fiscal Year
2013
Total Cost
$357,659
Indirect Cost
$117,303
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
Ehrentraut, Stefan F; Curtis, Valerie F; Wang, Ruth X et al. (2016) Perturbation of neddylation-dependent NF-κB responses in the intestinal epithelium drives apoptosis and inhibits resolution of mucosal inflammation. Mol Biol Cell :
Onyiah, Joseph C; Colgan, Sean P (2016) Cytokine responses and epithelial function in the intestinal mucosa. Cell Mol Life Sci 73:4203-4212
Colgan, Sean P; Campbell, Eric L; Kominsky, Douglas J (2016) Hypoxia and Mucosal Inflammation. Annu Rev Pathol 11:77-100
Kelly, Caleb J; Colgan, Sean P (2016) Breathless in the Gut: Implications of Luminal O2 for Microbial Pathogenicity. Cell Host Microbe 19:427-8
Campbell, Eric L; Kao, Daniel J; Colgan, Sean P (2016) Neutrophils and the inflammatory tissue microenvironment in the mucosa. Immunol Rev 273:112-20
Colgan, Sean P (2016) Targeting hypoxia in inflammatory bowel disease. J Investig Med 64:364-8
Saeedi, Bejan J; Kao, Daniel J; Kitzenberg, David A et al. (2015) HIF-dependent regulation of claudin-1 is central to intestinal epithelial tight junction integrity. Mol Biol Cell 26:2252-62
Aherne, C M; Saeedi, B; Collins, C B et al. (2015) Epithelial-specific A2B adenosine receptor signaling protects the colonic epithelial barrier during acute colitis. Mucosal Immunol 8:1324-38
Zheng, Leon; Kelly, Caleb J; Colgan, Sean P (2015) Physiologic hypoxia and oxygen homeostasis in the healthy intestine. A Review in the Theme: Cellular Responses to Hypoxia. Am J Physiol Cell Physiol 309:C350-60
Campbell, Eric L; Colgan, Sean P (2015) Neutrophils and inflammatory metabolism in antimicrobial functions of the mucosa. J Leukoc Biol 98:517-22

Showing the most recent 10 out of 51 publications