# Sex-differences in ACE2 Regulate Normal Tissue Toxicity During Gastrointestinal Acute Radiation Syndrome

> **NIH NIH U01** · MEDICAL COLLEGE OF WISCONSIN · 2024 · $546,000

## Abstract

SUMMARY
Our laboratory has recently reported sex-differences in morbidity during gastrointestinal acute radiation
syndrome (GI-ARS) with adult male rats having increased susceptibility to GI-ARS than age-matched female
rats. This finding is in line with a growing body of evidence from multiple labs which demonstrate GI radiation
sensitivity and response to candidate GI mitigators is sex dependent. Together, these data emphasize the
need for understanding how biological sex regulates normal tissue response to radiation and the consideration
of sex-based differences in MCM development.
In this application to RFA-AI-23-024 (Sex Differences in Radiation Research), we propose to evaluate whether
sex-differences in the regulation of the enzyme ACE2 may be an underlying driver of the observed sex-
difference in radiation sensitivity. Ace2 is an X-linked gene that may escape X-chromosome inactivation to
provide a “double-dosage” of ACE2 mRNA. Additionally, ACE2 mRNA transcription is known to be regulated
by the female estrogen hormone. We hypothesize elevated ACE2 expression and activity in the GI system of
female rats relative to age-matched males may confer a survival advantage during GI-ARS.
ACE2 enzyme activation promotes production of the peptide Ang(1-7) which mediates downstream signaling
via the GPCR Mas receptor (MasR). Ang(1-7) treatment following myelosuppressive radiation injury has been
shown to accelerate hematopoietic recovery and improves survival during ARS. Consistent with these studies,
our lab demonstrated pharmacologic ACE2 agonism with the small molecule diminazene aceturate (DIZE)
promotes survival in rodent models of GI-ARS, H-ARS and the delayed effects of acute radiation exposure
(DEARE). However, we have recently observed that DIZE-mediated mitigation effects during GI-ARS are
more pronounced in male rats than female rats.
Based on these data, we propose three Aims to comprehensively characterize the connection between
biological sex and ACE2 in the pathogenesis of the GI injury. Aim 1 will evaluate whether agonism of the
ACE2/Ang(1-7)/MasR pathway promotes similar GI protection in male and female rats. Aim 2 will determine if
loss of estrogen via ovariectomy alters ACE2 activation and impacts the established sex-differences in GI-
ARS. Finally, in Aim 3, we will characterize the tissue-specific necessity for ACE2 in the gut using inducible
Cre-loxP mouse models. This work will be conducted using dual approaches of pharmacologic and genetic
loss of function studies in well-validated, in vivo animal models of acute radiation injury.
This work will advance our understanding of the mechanisms which contribute to sex-differences in
radiosensitivity. Additionally, as there are currently no FDA-approved medical countermeasures (MCM) for
GI-ARS, our proposed development of ACE2 agonist DIZE as a MCM for GI-ARS has high translational
relevance.

## Key facts

- **NIH application ID:** 10916636
- **Project number:** 1U01AI183904-01
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Heather A Himburg
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $546,000
- **Award type:** 1
- **Project period:** 2024-06-18 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10916636

## Citation

> US National Institutes of Health, RePORTER application 10916636, Sex-differences in ACE2 Regulate Normal Tissue Toxicity During Gastrointestinal Acute Radiation Syndrome (1U01AI183904-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10916636. Licensed CC0.

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