# Unraveling the corneal and retinal mechanisms of chemical injury

> **NIH NIH R56** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2023 · $498,248

## Abstract

Abstract:
Chemical threat agents can potentially be weaponized to cause mass casualties and such
egregious events are of grave concern to homeland security. Sulfur mustard and its analog
nitrogen mustard (NM) are vesicants that cause severe acute injury to ocular tissues and
ultimately develop fibrotic scarring leading to vision loss. As medical treatments for vesicant injury
have yet to be developed for paucity of a complete understanding of their pathophysiological
mechanisms, this unmet medical need remains an urgent matter of importance to the Chemical
Countermeasures Research Program (CCRP). Under an exploratory R21 grant funded by the
CCRP, we have discovered that NM injury to the mouse cornea triggers a rapid and profound
induction of retinal gliosis. This retinal response is coordinated in reactive Muller glia with
activation of the posttranslational modification (PTM) known as citrullination. This finding extends
our prior results showing that retinal hypercitrullination driven by the enzyme peptidyl arginine
deiminase (PAD)-4 is a shared pathological feature that is common to a number of different injury
and disease paradigms. But critical gaps remain regarding the molecular steps involved in the
PAD-hypercitrullination axis. As other published reports have shown that NM crosslinks tumor
suppressor p53 and the p53 DNA damage pathway interacts with PAD4, these data provokes an
interesting idea whether these two major orchestrators of pathological response are tied to
activating hypercitrullination in both the cornea and retina. In this R01 grant proposal, we will
investigate the acute and chronic (delayed) injury mechanisms of NM across the cornea and retina
in mouse and rat models. Specifically in Aim 1, we will investigate the molecular mechanisms of
the p53-PAD axis involving corneal hypercitrullination and identify the relevant PAD using both in
vivo and cell culture models to study NM injury. In Aim 2, we will characterize the corneal and
retinal citrullinomes of NM injury using proteomics by examining the temporal changes over the
early and chronic stages. This study will allow us to identify key PAD substrates of acute and
chronic injury states, permitting us to decipher the evolution of key protein players modified by
citrullination in perpetuating corneal and retinal pathology. We believe this in-depth investigation
into hypercitrullination in the NM injured eye could unravel novel mechanisms and druggable PAD
targets that would be critical for drug discovery to combat chemical injury to the human eye. Given
that PADs are already being investigated as targets for several common diseases, the likelihood
of clinical drugs becoming available for humans in the near future makes this an attractive target
class for further mechanistic assessment.

## Key facts

- **NIH application ID:** 10882069
- **Project number:** 1R56EY035219-01
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** ROYCE MOHAN
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $498,248
- **Award type:** 1
- **Project period:** 2023-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10882069

## Citation

> US National Institutes of Health, RePORTER application 10882069, Unraveling the corneal and retinal mechanisms of chemical injury (1R56EY035219-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10882069. Licensed CC0.

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