# UAB Research Center of Excellence in Arsenicals

> **NIH NIH U54** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $3,760,306

## Abstract

Vesicants were developed as chemical weapons to debilitate the military and civilian populations during World
War-I/II as these chemicals cause rapid and severe painful inflammatory and blistering responses in the skin.
These agents include mustards and arsenicals. Among them sulfur mustard and lewisite were weaponized as
single agents as well as a mixture of the two. The only known antidote for arsenicals is British Anti-lewisite (BAL),
which is not very effective and itself is highly toxic. The molecular pathogenesis of arsenicals remains poorly
understood, which is also an important impediment in developing mechanism-based antidotes for mitigating the
toxicity of these chemicals. Therefore, the major goal of this U54 Center is to develop mechanism-based highly
efficacious antidotes against chemical war relevant arsenicals namely lewisite, diphenylchloroarsine,
diphenylcynoarsine and diethylchloroarsine (as prioritized by the NIH CounterACT program). The scientific
premise of this investigation lies in the strong and compelling preliminary data demonstrating that epigenetic
regulation of molecular signaling pathways regulate arsenicals-mediated onset of aberrant and robust cutaneous
inflammation and tissue damage. These data also indicate that recruitment of bromodomain 4 (BRD4) to
promotor region of inducible genes could be involved in the pathogenesis of arsenicals-mediated multi-organ
damage including skin, lung and kidney. To test this hypothesis, we have developed a murine model that
recapitulates the tissue damaging acute as well as delayed responses of these arsenicals described in exposed
humans. Three specific aims are proposed. In specific aim-1, studies are focused to fully characterize the animal
model of arsenicals-mediated acute and delayed cutaneous, pulmonary and renal damage following skin
exposure to these chemical vesicants. This will be achieved by defining molecular biomarkers and epigenetic
marks associated with the progression of the damage. Specific aim-2 will define molecular mechanism of
arsenicals' toxicity with an objective for developing novel mechanism-based pharmacological inhibitors that can
mitigate arsenicals' toxicity including cutaneous, pulmonary and renal injury. Studies in specific aim-3 are related
to defining window of effective therapeutic intervention of pharmacological inhibitors of BDR4 in terms of
suppressing cutaneous, pulmonary and renal damage following skin exposure to these chemicals. The outcome
of this study will lead to paradigm shift discovery of antidotes against arsenicals which could block effectively
multi-organ damage, morbidity, and mortality. These inhibitors could also provide efficacy against other similar
chemicals. In addition, based on the discovery of novel molecular targets, synthesis and characterization of small
molecules will done by the Drug Discovery and Development Core. These antidotes could easily be delivered
subcutaneously by auto-injectable FDA approved devices in c...

## Key facts

- **NIH application ID:** 10249107
- **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:** $3,760,306
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10249107

## Citation

> US National Institutes of Health, RePORTER application 10249107, UAB Research Center of Excellence in Arsenicals (5U54ES030246-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10249107. Licensed CC0.

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