# The Role of HIF2-Induced Wnt5a in Small Intestine Regeneration after Radiation Injury

> **NIH NIH F31** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $33,010

## Abstract

Project Summary/Abstract
Radiation-induced gastrointestinal syndrome (RIGS) occurs when the small intestines are exposed to high doses
of radiation. Radiation injury to the intestinal stem cell (ISC) and endothelial compartments impair intestinal
regeneration, cause loss of epithelial integrity and mucosal barrier dysfunction. This in turn leads to
malabsorption, dehydration, electrolyte imbalances, bacterial translocation, sepsis, and often death.
Furthermore, radiation therapy for abdominal tumours is challenging because the small intestine is exquisitely
radiosensitive. The intestine’s self-renewal ability and susceptibility to radiation derive from the rapid-cycling
ISCs in the crypts. The crypt base columnar (CBC) cells give rise to all the intestinal cell lineages, which are
broadly categorized as absorptive or secretory cells. Enteroendocrine cells, which are part of the secretory niche,
have been shown to be cryptogenic and injury-inducible. There is also evidence that secretory progenitor cells
can revert to CBCs when there is intestinal injury. Our preliminary data indicate that radiation induces the
expression of markers associated to the secretory niche. However, the dynamics of the secretory niche plasticity
and their relation to CBC cells in the context of radiation injury remain unclear. Moreover, there are no therapies
to prevent, mitigate, or treat RIGS or even modest intestinal radiation injury. The EGLN family are cellular oxygen
sensors that regulate cell survival and metabolism through the degradation hypoxia-inducible factors (HIFs).
HIFs are known to induce tissue remodelling, increase epithelial integrity, stimulate intestinal angiogenesis, and
promote stem cell survival, all of which are essential for response to radiation injury. Additionally, HIFs regulate
genes required for intestinal barrier function. Our group has shown that stabilization of HIF2, but not HIF1,
through inhibition of the EGLN proteins mitigates and protects against RIGS in mice. Yet, the mechanisms by
which HIF2 confers this radioprotection remain poorly studied. To gain insight into this mechanism, we performed
RNA-seq of HIF2-overexpressing intestinal organoids. We identified Wnt5a, a non-canonical WNT, as a direct
transcriptional target of HIF2, but not HIF1. Interestingly, other groups have shown Wnt5a improves colonic crypt
regeneration following mechanical injury. We also found that knock-out of Wnt5a decreased the clonogenic
potential of ISCs. Thus, we hypothesize that HIF2 induces intestinal regeneration after radiation injury by
inducing Wnt5a expression to promote ISC survival. We will examine this hypothesis in two aims. In aim 1
we will determine if HIF2 binds and activates the WNT5A promoter. We will also test if Wnt5a is necessary and
sufficient for HIF2-mediated intestinal radioprotection both in vitro and in vivo. In aim 2 we will identify which ISC
populations are radioprotected by the HIF2/Wnt5a axis. To do so, we will perform lineag...

## Key facts

- **NIH application ID:** 9905311
- **Project number:** 5F31DK121384-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Carolina Jannet Garcia Garcia
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $33,010
- **Award type:** 5
- **Project period:** 2019-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9905311

## Citation

> US National Institutes of Health, RePORTER application 9905311, The Role of HIF2-Induced Wnt5a in Small Intestine Regeneration after Radiation Injury (5F31DK121384-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9905311. Licensed CC0.

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