# Sex specific differences in intestinal radiosensitivity

> **NIH NIH U01** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2024 · $532,828

## Abstract

Project Summary
Role of sex as a confounder in radiation research and its implication in radiological and nuclear countermeasure
development has not been addressed well. Currently, there is a need for strategies that mitigate Gastrointestinal
acute radiation syndrome (GI-ARS). However, sex specific differences in intestinal radiosensitivity have not been
determined. Intestinal epithelium is one of the most radiosensitive tissue due to their high self-renewal rate.
Radiation-induced damage in intestinal epithelium results in loss of crypt progenitor cells, damage of crypt villus
structure resulting in impaired mucosal barrier function, inflammation, bacterial influx and sepsis. Our previous
study clearly demonstrated that repair and regeneration of intestinal stem cells (ISCs) is crucial to mitigate
radiation-induced toxicity of intestinal epithelium and thereby mitigation of GI-ARS. We have observed that male
intestinal epithelium is more radiosensitive compared female with higher level of mitochondrial oxidative
phosphorylation, reactive oxygen species production and inflammation. However, these differences are not
related to sex hormone as sex steroid hormones have no direct effect on intestinal epithelium. Mitochondrial
ROS production is directly related to mitochondrial pyruvate transport and oxidation. We observed that
expression of mitochondrial pyruvate carrier (MPC) and pyruvate oxidation is higher in male intestinal epithelium
than female. Inhibition of MPC significantly reduces the mitochondrial ROS production, minimize radiation
induced epithelial damage and mucosal inflammation and thereby mitigate GI-ARS in both sexes of mice. We,
therefore, hypothesize that mitochondrial pyruvate transport could be a potential target for mitigation of GI-ARS.
In this proposal we will first examine the involvement of mitochondrial pyruvate metabolism in sex specific
differences in ISC radiosensitivity by using pharmacological or genetic modulation of MPC (Specific aim 1). Next,
we will examine weather inhibition of MPC can mitigate radiation induced acute mucosal inflammation (Specific
aim 2) and reduce sex specific differences in radiation induced mucosal inflammation. Finally, we will
characterize the MPC inhibitor treatment with a determination of an optimum dose and schedule for mitigation
of GI-ARS in both male and female mice. We will examine the general applicability of this strategy in young and
aged animals. Determination of mechanism of action and dose optimization study of MPC inhibitor will facilitate
MPC inhibitor as a medical countermeasure against radiation under the FDA’s Animal Rule.

## Key facts

- **NIH application ID:** 10923646
- **Project number:** 1U01AI183950-01
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** Subhrajit Saha
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $532,828
- **Award type:** 1
- **Project period:** 2024-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10923646

## Citation

> US National Institutes of Health, RePORTER application 10923646, Sex specific differences in intestinal radiosensitivity (1U01AI183950-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10923646. Licensed CC0.

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