# Late/chronic corneal injury following threat chemical exposure

> **NIH NIH R01** · UNIVERSITY OF MISSOURI-COLUMBIA · 2024 · $446,228

## Abstract

Abstract
Exposure of Carbofuran (CF; a pesticide) and Chlorine (Cl2; a bleaching and warfare agent) to humans is a major
public health issue. Over 3 million people exposed to CF/Cl2 show high ocular morbidity. A major gap in
knowledge is lack of mechanistic data “how CF/Cl2 exposure causes corneal injury and vision loss”? We test a
novel hypothesis that mTORC1-mediated dysfunctional autophagosome formation and lysosomal biogenesis
are a dominant operating mechanism for corneal damage from exposure of these threat chemicals (CF/Cl2).
Autophagy and lysosomal biogenesis play a key role in corneal homeostasis and transparency maintenance.
Our hypothesis is based on a human-patient study identifying defective autophagy the cause of slow and
progressive corneal thinning and vision loss in keratoconus patients. Pilot studies performed with mice and donor
human corneas strongly supports our novel hypothesis. The main goal of this project is to test our hypothesis
employing highly rigorous approach using 2 threat chemicals (CF and Cl2) and 2 animal species (C57BL/6J mice
and New Zealand White rabbits) and applicability of postulated mechanism in human using donor human cornea
derived organ culture and primary cell culture models using two entirely independent but integrated specific aims.
Aim-1 defines clinical signs and underline mechanism of late/chronic corneal toxicity caused by CF exposure to
the eye using 3 sub-aims: (1a) records clinical signs and changes in the phenotype and density of corneal
epithelial, stromal keratocytes, and endothelial cells in CF +/- exposed eyes of live rabbits and mice in vivo every
two weeks interval with slit-lamp, HRT3-RCM confocal, Specular, and Spectralis optical coherence tomography
microscopy system until 6 months, (1b) defines the mechanism by analyzing autophagosomal and lysosomal
signature genes (ATGs, LC3, SQSTM1/p62, LAMP1, mTORC1, TFEB, & vATPase) in CF +/- exposed corneas
of 2 species collected at 1, 2, 4, and 6 months, and (1c) verifies applicability of postulated mechanism in human
using cadaver corneas. Aim-2 defines clinical symptoms and underline mechanism of late/chronic corneal
toxicity caused by Cl2 exposure to the eye using 3 sub-aims: (2a) records clinical signs and changes in the
phenotype and density of corneal epithelial, stromal keratocytes, and endothelial cells in Cl2 +/- eyes of live
rabbits and mice in vivo, (2b) elucidates Cl2-induced corneal damage by studying autophagosomal and
lysosomal signatures stated in aim-1b in Cl2 +/- corneas of 2 species, and (2c) verifies applicability of mechanism
in humans using control donor human corneas employing an experimental approach and techniques stated in
Aim-1a-c. With proposed studies, we expect to define start time, extent, and duration of symptoms after CF and
Cl2 exposure in live animals, role of mTORC1 mediated autophagic events in CF/Cl2 exposed corneas and
signature autophagosomal and lysosomal genes linked to CF/Cl2 mediated corneal toxicit...

## Key facts

- **NIH application ID:** 10903728
- **Project number:** 5R01EY034319-03
- **Recipient organization:** UNIVERSITY OF MISSOURI-COLUMBIA
- **Principal Investigator:** Suneel Gupta
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $446,228
- **Award type:** 5
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10903728

## Citation

> US National Institutes of Health, RePORTER application 10903728, Late/chronic corneal injury following threat chemical exposure (5R01EY034319-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10903728. Licensed CC0.

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