# Toxic Mechanisms of Vesicating Chemicals in the Eye

> **NIH NIH R01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2024 · $453,981

## Abstract

PROJECT SUMMARY/ABSTRACT
The cornea is highly susceptible to injury from chemotoxic vapors. Long-term prognosis after severe corneal
injury is poor, involving impaired vision, progressive corneal decompensation and neovascularization. In
particular, ocular injuries caused by the formation of chemical adducts between biological molecules and highly
reactive organic toxic industrial materials (TIMs) remain poorly characterized. The ocular threat caused by
organic TIMs was illustrated in Bhopal, India in 1984, when the accidental release of methyl isocyanate resulted
in over 3,700 deaths and 500,000 casualties, with 4,000 survivors suffering permanently disabling ocular
pathophysiologies such as corneal scars, opacities and cataracts. In this proposal we will characterize the dose-
dependent, acute and long-term effects of diverse, highly reactive organic TIMs on corneal injury and recovery.
The approach integrates in vivo methods developed to study corneal toxicities elicited by the archetypal vesicant
sulfur mustard with ex vivo approaches pioneered to study the corneal effects of exposure to diverse chemotoxic
agents. We will focus on TIMs that are widely availability in large quantities and thus pose a large-scale
chemotoxic threat following accidental or purposeful release. In the first aim, we will integrate the ex vivo depth-
of-injury exposure model with our well-described vapor cap exposure system to determine TIM vapor doses that
produce mild and severe corneal lesions in isolated rabbit eyes. In the second aim, we will translate dose
estimates to in vivo eyes in rabbits and study molecular, clinical and pathophysiological mechanisms of corneal
injury over 8 weeks. In the final aim, we will compare and contrast (a) acute changes in gene expression in
human and rabbit eyes exposed to superficial and penetrating doses of three TIMs and (b) study longitudinal
changes in gene expression in vivo following exposure to penetrating doses of 3 TIMs. By studying the toxic
effects of diverse reactive TIMs, we will develop a threat profile based on dose, tissue-specific cytotoxicities,
pathophysiological progression and efficacy of available therapeutics. In addition to identifying toxicological
mechanisms and expanding our understanding of chemotoxic injury in the cornea, these studies will inform risk
assessments and exposure management plans for these highly toxic organic TIMs and related chemicals.

## Key facts

- **NIH application ID:** 10906754
- **Project number:** 5R01EY034139-03
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Patrick Michael McNutt
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $453,981
- **Award type:** 5
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10906754

## Citation

> US National Institutes of Health, RePORTER application 10906754, Toxic Mechanisms of Vesicating Chemicals in the Eye (5R01EY034139-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10906754. Licensed CC0.

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