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cGas-STING pathway based medical countermeasure for vesicant skin injury

Award Number: R21AR087354
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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cGas-STING pathway based medical countermeasure for vesicant skin injury - The U.S. Department of Homeland Security (DHS) has identified about 200 highly toxic and hazardous industrial and warfare chemical agents as Chemicals of Concern (CoC), among them is a category of chemicals called vesicants. Skin exposure to these chemicals causes painful inflammatory and blistering tissue injury. Arsenicals such as lewisite and others are rapid-acting vesicants developed as chemical weapons. In earlier studies, we developed highly relevant and well-characterized animal models of arsenical exposure for recapitulating severe painful inflammatory, tissue-damaging, and other pathophysiological responses that lead to morbidities and mortality in humans. Our data revealed the initial biochemical pathways instrumental in triggering pathogenesis. In this regard, identification of DNA damage, activation of unfolded protein response (UPR) signaling, role of stress granule and dysregulation of RNA binding proteins causing inflammation are our important leads. However, the knowledge of the exact molecular injury driver pathway remains elusive, which is critical to develop highly potent antidote for these chemicals. Using murine models that developed in our laboratory, we propose to test the hypothesis that arsenicals cause skin inflammation and blistering involving type-I interferon regulating signaling cGAS-STING pathway and its inhibition by small molecules could provide a highly effective mechanism-based drug for attenuating toxic manifestations of arsenicals. Importantly, cGas-Sting pathway has recently been identified to be associated with both acute human injury followed by several delayed disease manifestations. Therefore, we believe that understanding the regulation of this pathway may not only be crucial in defining acute skin injury mechanism but will also be a basis for uncovering long-term disease susceptibilities in exposed populations. To test this hypothesis, two specific aims are proposed. In specific aim 1, we will define if cGAS-Sting pathway is regulated by lewisite and other arsenicals and its activation leads to the pathogenesis of skin disruption, blistering and inflammation. The specific aim 2 is focused on screening various clinically relevant and other small molecule inhibitors of cGas-Sting pathway. This will be followed by determining their in vivo potential to attenuate the expression of cGas-Sting signaling proteins, depicting clinical biomarkers of injury, and -associated pathogenesis of blistering, and inflammation. Establishing the mechanism of efficacy of these inhibitors will also be a long-term goal as will be required for obtaining IND status of our lead compound from FDA. Uncovering the underlying molecular mechanism and subsequent development of highly effective and easily administrable antidotes/drugs for use in unlikely mass casualty situation as medical countermeasure (MCM) is our ultimate objective. In summary, we believe that the successful candidate will suppress the cutaneous injury, associated morbidities and delayed effects as well. The PI, with a highly competent co- investigator of this R21, are highly experienced. The PI has been in a leadership position for more than two decades.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $408,374 )
2026	2026	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	8/21/2026	NEW	$408,374
														Subtotal = $408,374

Grand Total All Awards = $408,374

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cGas-STING pathway based medical countermeasure for vesicant skin injury

Award Number: R21AR087354

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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