# STING-dependent Intestinal Regeneration upon Radiation Injury

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2024 · $474,148

## Abstract

Summary
The intestinal epithelium is the fast renewing adult tissue and highly sensitive to genotoxic agents such as
radiation and chemotherapy. Acute gastrointestinal (GI) injury can be lethal in radiation victims or dose-limiting
in cancer patients, which can lead to chronic barrier dysfunctions that impair the quality of life in survivors.
Radiation induced enteritis was first described in 1897, while there is still no FDA-approved treatment, in part
due to limited understanding of how intestinal stem cell (ISC) injury is coupled to regeneration. We and others
have established that the cell-intrinsic p53 pathway governs ISC intestinal regeneration using high dose total
body irradiation (TBI) and abdominal irradiation (ABI) (with major bone marrow sparing) models. Our recent data
indicate a novel role of “Niche” signals including innate immune signaling in intestinal regeneration. We
demonstrated that a highly temporal and dynamic acute and local inflammation is “reparative”, which is activated
by Stimulator of Interferon Genes (STING)-dependent Type 1 Interferon (IFN) response following delayed mitotic
death to promote intestinal regeneration. Surprisingly, non-bone marrow (BM) STING plays a major role in acute
crypt inflammation and regeneration. Remarkably, a single administration of IFNβ given 48 hours after TBI or
ABI improved survival and intestinal regeneration in STING-deficient mice and WT mice. These data support
that inducible production of IFNβ is necessary and sufficient to promote ISC and intestinal barrier recovery from
radiation injury through a novel niche and immune-dependent mechanism. We will test this hypothesis with three
specific aims using in vivo and ex vivo mouse and human intestinal organoids coupled with in depth mechanistic
dissection. SA1. Dissect STING-dependent local IFNβ production in acute crypt regeneration. SA2. Elucidate
STING-dependent immune targets for ISC regeneration. SA3. Establish IFNβ as a novel target to enhance long-
term ISC and intestinal barrier recovery from radiation injury. The proposed studies will provide novel
mechanistic insights in radiation-induced ISC regeneration through epithelial and immune interactions in the
niche, and establish temporal STING/IFNβ signaling as a novel and normal tissue selective target to treat
radiation-induced acute intestinal damage.

## Key facts

- **NIH application ID:** 10799622
- **Project number:** 5R01CA260900-04
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Jian Yu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $474,148
- **Award type:** 5
- **Project period:** 2023-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10799622

## Citation

> US National Institutes of Health, RePORTER application 10799622, STING-dependent Intestinal Regeneration upon Radiation Injury (5R01CA260900-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10799622. Licensed CC0.

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