# Sex differences in delayed development of gastrointestinal fibrosis after acute radiation exposure

> **NIH NIH U01** · DUKE UNIVERSITY · 2024 · $563,500

## Abstract

Abstract
 In case of radiation accidents or nuclear warfare, exposure of the small intestine and colon to high-dose
irradiation results in delayed injury, manifested by an increase in fibrosis, that significantly impacts organ
function. There are no current FDA-approved medical countermeasures to prevent, mitigate, or treat delayed
radiation injury of the small intestine and colon. However, one major challenge for the development of such
therapies is to understand how fibrosis associated with DEARE (Delayed Effects of Acute Radiation Exposure)
is impacted by biological sex, as recent studies suggest that females may be more sensitive to delayed
radiation-induced fibrosis compared to males. Our long-term goal is to uncover the mechanisms underlying the
effects of biological sex on acute and long-term radiation injury of the GI tract. Type I IFN has been proposed
as a potential mitigator of acute radiation injury to the intestine by promoting epithelial regeneration.
Furthermore, Type I IFN is activated in the intestine and colon following acute radiation injury and is
persistently upregulated in our model of DEARE. In preliminary studies, we evaluated radiation-induced
delayed colonic fibrosis in male and female Irgm1-/- mice that are known to potently activate Type I IFN and
found that germline Irgm1 deletion results in substantially greater colonic fibrosis in females compared to
males. Therefore, in this application, we hypothesize that Type I Interferon signaling, while preventing acute
radiation injury to the GI tract, promotes long-term intestinal fibrosis to a greater degree in females vs. males.
We will test this hypothesis through the following Specific Aims: Aim 1: To determine the molecular
mechanisms of sex-dependent, Type I Interferon signaling in radiation-induced fibrosis. Aim 2: To determine
the cellular origins of sex-dependent, radiation-induced fibrosis. Aim 3: To determine the efficacy of FDA
approved Type I Interferon inhibitors to prevent the development of radiation-induced intestinal fibrosis in
females vs. males. Together, these studies will reveal novel mechanisms by which activation of Type I
Interferon promotes the development of chronic submucosal fibrosis in the gastrointestinal tract in sex-
dependent manner, which is a major complication of survival from gastrointestinal acute radiation syndrome
(GI-ARS). These results will inform the future development of mitigators of DEARE in female and male
populations.

## Key facts

- **NIH application ID:** 10923411
- **Project number:** 1U01AI183940-01
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Chang-Lung Lee
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $563,500
- **Award type:** 1
- **Project period:** 2024-06-03 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10923411

## Citation

> US National Institutes of Health, RePORTER application 10923411, Sex differences in delayed development of gastrointestinal fibrosis after acute radiation exposure (1U01AI183940-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10923411. Licensed CC0.

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