# Hypoxia, HIF, and Mucosal Inflammation

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2024 · $426,981

## Abstract

Tissue metabolism in ongoing inflammatory responses is an area of significant interest. Within the mucosa,
changes in metabolism are associated with shifts in availability of O2 and the expression of O2-sensitive genes,
particularly those regulated by the transcription factor hypoxia-inducible factor (HIF). As work in progress, we
have focused on understanding molecular pathways and functional endpoints initiated by the stabilization of
intestinal epithelial cell (IEC) HIF. These studies have revealed that diminished O2 availability (hypoxia) is a
major contributing factor to the resolution of intestinal inflammation. Studies from cultured cell systems, animal
models and human tissues have revealed that metabolites generated within the inflammatory
microenvironment are central to barrier regulation and anti-microbial function. Results from animal models of
intestinal inflammation have demonstrated an almost uniformly beneficial influence of HIF-1 stabilization on
disease outcomes, particularly related to the resolution of mucosal inflammation. Nonetheless, we believe that
there is significant untapped potential within this field of study. We hypothesize that HIF-1 and HIF-2-
dependent signaling evokes a pro-resolving epithelial phenotype during intestinal inflammation. Three
synergistic specific aims are proposed. In Aim 1, we will distinguish the select regulation of epithelial junctional
proteins by HIF-1 and HIF-2. Aim 2 will develop and test a new class of HIF prolyl hydroxylase inhibitors
(PHDi) on mucosal barrier function and wound healing. Specific Aim 3 will evaluate in vivo endpoints of
pharmacological HIF stabilization. Results from these experiments will provide new insights into innate
regulation of mucosal barrier and an expanded role for PHDi in the resolution of mucosal inflammation. It is our
hope that extensions of this will lead to the identification of new therapeutic targets for mucosal inflammatory
disease.

## Key facts

- **NIH application ID:** 10817192
- **Project number:** 5R01DK050189-30
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Sean P Colgan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $426,981
- **Award type:** 5
- **Project period:** 1995-09-25 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10817192

## Citation

> US National Institutes of Health, RePORTER application 10817192, Hypoxia, HIF, and Mucosal Inflammation (5R01DK050189-30). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10817192. Licensed CC0.

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