# Ocular mustard keratopathy elicits induced autophagy, which is detrimental to the cornea

> **NIH NIH R56** · NORTHWESTERN UNIVERSITY · 2024 · $468,734

## Abstract

PROJECT SUMMARY/ABSTRACT
The long-term goal of this project is to understand the pathological mechanisms of sulfur mustard gas
keratopathy (MGK) in the cornea. Sulfur mustard (SM) is an alkylating agent that has been used as a chemical
warfare agent. SM exposure to the eye results in acute corneal injury. A subset of patients, particularly those
with high exposure levels, develop chronic or delayed symptoms, which is known as MGK. Thus far, there are
no specific treatments available to stop or reverse the detrimental effects of MGK. One of reasons for the lack
of a specific treatment is that the mechanisms of MGK are not fully understood. Autophagy is a process by
which cells break down and recycle their own cellular components, including damaged proteins and organelles.
Even though autophagy has been recognized as a fundamental cellular process against stress, autophagy can
play beneficial or detrimental roles depending on the context. In the cornea, it has been demonstrated that in
response to most of stresses, autophagy plays beneficial roles to protect tissue homeostasis. Our laboratory
and many other investigators have been focusing on such protective roles of autophagy in the cornea.
However, the detrimental role of autophagy in the cornea has not been studied. Interestingly, when we
investigated the role of autophagy in corneal injury due to chemical exposure, we found that nitrogen mustard
(NM), an analog of sulfur mustard, induced a unique autophagy, which plays a harmful role in the cornea. It
has been shown that the liberation of Beclin1, a key regulator in induction of autophagy, from Beclin1-Bcl2
complex can induce autophagy. Our preliminary data suggest that after NM exposure, sequestration of Beclin1
in Beclin1-Bcl2 complex attenuates NM-induced corneal inflammation. Therefore, we hypothesize that corneal
mustard exposure induces autophagy via liberating Beclin1 from Beclin1-Bcl2 complex and such induced
autophagy promotes corneal inflammation and contributes to MGK. In Aim 1, we will explore: (i) whether NM
exposure will affect Beclin1-Bcl2 binding in vitro and in vivo; and (ii) whether manipulation of Beclin1-Bcl2
binding will affect NM-induced autophagy in cornea. In Aim 2, we will capitalize on our ability to conduct gain-
and loss-of-function studies of induced autophagy in mice. We will inhibit induced autophagy via either
reducing Beclin1 expression or preventing the disassociation of Beclin1-Bcl2 complex in vivo. We will also
enhance induced autophagy via preventing the binding of Beclin1 and Bcl2 in vivo. We will utilize these
genetically modified mouse models to determine whether the detrimental effects of NM exposure in cornea will
be: (i) attenuated by inhibition of induced autophagy, while (ii) increased by enhancement of induced
autophagy. Knowledge from this project will reveal the pathological importance of induced autophagy in
corneal MGK and will form the foundation for the development of novel therapies for this ...

## Key facts

- **NIH application ID:** 11123560
- **Project number:** 1R56EY036320-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Han Peng
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $468,734
- **Award type:** 1
- **Project period:** 2024-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11123560

## Citation

> US National Institutes of Health, RePORTER application 11123560, Ocular mustard keratopathy elicits induced autophagy, which is detrimental to the cornea (1R56EY036320-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11123560. Licensed CC0.

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