# HIF-Regulated Autophagy in Host-microbe Interactions

> **NIH VA IK2** · VA EASTERN COLORADO HEALTH CARE SYSTEM · 2024 · —

## Abstract

Inflammatory bowel disease (IBD) is a family of conditions characterized by chronic, relapsing
inflammation of the gastrointestinal tract. IBD is especially prominent amongst military veteran populations,
with one of the highest hospitalization rates of tracked diseases (>100,000 hospitalizations from 1975-2006)
and accompanying high rates of hospital readmission. A recent study of the incidence of IBD in the veteran
population has found that the incidence of IBD is 2-10 times greater than non-service members, showing a
high degree of correlation with life stressors, and is on the increase in certain populations. Although treatments
for IBD do exist, they are plagued by imperfections such as debilitating side effects (e.g., immunosuppression)
and loss in effectiveness over time. Development of novel therapeutics is hampered by a poor understanding
of the molecular mechanisms of IBD pathogenesis; consequently, a need exists to better understand the
molecular pathophysiology of IBD to inform the development of novel therapies.
 One of the major molecular pathways associated with IBD is macroautophagy, hereafter referred to as
autophagy. Autophagy is a conserved eukaryotic system wherein intracellular contents are recycled through
the lysosome. Autophagy genes have been identified as IBD risk factors, and defects in autophagy have been
experimentally shown to confer greater susceptibility to colitis in animal models. However, a complete
understanding of the mechanism by which autophagy regulates IBD disease susceptibility is not known.
Importantly, however, defects in autophagy appear to compromise normal host-microbe interactions at the
intestinal interface by decreasing anti-microbial autophagy (“xenophagy”).
 Preliminary studies from our group have implicated autophagy in the proper function of intestinal
epithelial cells (IECs). ChIP-chip analysis of hypoxia-treated IEC showed that several autophagy genes
contained hypoxia-inducible factor (HIF) transcription factor binding sites in their promoter regions. HIF is a
family of transcription factors responsible for the cellular response to low oxygen tensions and previously
shown to be essential for intestinal homeostasis. These data also suggest that autophagy genes are
transcribed preferentially by the HIF-1α isoform, as opposed to HIF-2α. In addition, hypoxia treatment of IECs
increased autophagic flux in vitro, suggesting an increase in functional autophagy to hypoxia stimulation in
addition to a transcriptional response. Finally, knockdown of HIF-1α increased susceptibility to the model
intracellular bacterium Salmonella Typhimurium, suggesting a functional role for HIF in regulating xenophagy.
Based on these and ongoing studies, we hypothesize that HIF-1α promotes xenophagy in the intestinal
epithelium to regulate host-microbe interactions.
 To test this hypothesis, we propose three distinct but interrelated specific aims. We first propose to
characterize epithelial HIF-dependency of autophag...

## Key facts

- **NIH application ID:** 10585513
- **Project number:** 1IK2BX006088-01
- **Recipient organization:** VA EASTERN COLORADO HEALTH CARE SYSTEM
- **Principal Investigator:** ALEXANDER Shea DOWDELL
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2023-10-01 → 2028-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10585513

## Citation

> US National Institutes of Health, RePORTER application 10585513, HIF-Regulated Autophagy in Host-microbe Interactions (1IK2BX006088-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10585513. Licensed CC0.

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