# Project 1: Novel Pharmacological Inhibitors of Chemical Vesicants-mediated Cutaneous Injury

> **NIH NIH U54** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $719,082

## Abstract

The class of chemical war-threat agents known as vesicants include among others arsenicals and mustard
agents. Stockpiles of weaponized arsenic-based vesicants developed for World War II still exist. Recently,
vesicants have been used against civilian populations in Iraq and Syria and caused extensive morbidities and a
few casualties. Cutaneous exposure to arsenicals causes vesicular skin lesions, blisters, and painful cutaneous
inflammation, which progresses to multi-organ tissue disruption and death. Four major arsenicals, lewisite,
diphenylchlorarsine, diphenylcyanoarsine and diethylchloroarsine, have been identified as potential threat
chemicals by NIH CounterACT program for which antidotes/agents are highly sought. However, the mechanisms
by which these arsenicals manifest such robust deleterious effects in the skin remain undefined. We have
recently developed a highly sensitive murine model of cutaneous arsenical exposure, which recapitulates skin
pathology of humans exposed to these chemicals. Our preliminary studies indicate that the acute inflammatory
and tissue damaging effects caused by arsenicals are mediated through the rapid onset of epigenetic
modifications and chromatin remodeling via histone lysine hyperacetylation. In this regard, bromodomain 4
(BRD4), a reader of histone acetylation marks is considered to be one of the potent transcriptional regulator of
inducible inflammatory genes besides others. In this Project-I of U54, we propose to investigate histone
acetylation-based epigenetic alterations involved in the molecular pathogenesis of skin lesions and development
of antidotes that can block arsenical-induced cutaneous injury. Three specific aims are proposed: 1: To
characterize histone acetylation and chromatin remodeling-associated with arsenical exposure. This data will
provide a correlation between the spatiotemporal regulation of histone acetylation and underlying arsenicals-
induced cutaneous injury. After establishing these changes in murine skin we will confirm the molecular
pathogenesis of acute skin injury by arsenicals in minipig; 2: To unravel the molecular mechanism by which
arsenicals-mediated histone acetylations affect inflammatory and blistering responses. We will probe the
mechanisms by which arsenicals induce BRD4 activation. 3: To define the window of therapeutic intervention
of arsenicals-mediated tissue damage by administering BRD4 inhibitors. Our goal is to fully characterize the
kinetics of action and assess the therapeutic window of time (30, 60 or 120 min after exposure to arsenicals) in
which these BRD4 inhibitors are able to reverse arsenical-induced molecular changes and underlying skin
inflammation/blistering. This project will integrate with projects II, III, and scientific cores as animal tissues will
be shared from topically exposed animals. Therapies successful in reversing skin inflammation/damage will also
be verified for the diminution of lung and kidney injury. Successful completion of t...

## Key facts

- **NIH application ID:** 10249113
- **Project number:** 5U54ES030246-04
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Mohammad Athar
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $719,082
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10249113

## Citation

> US National Institutes of Health, RePORTER application 10249113, Project 1: Novel Pharmacological Inhibitors of Chemical Vesicants-mediated Cutaneous Injury (5U54ES030246-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10249113. Licensed CC0.

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