Tuesday, July 1, 2025 7/1/2025

Platelets in radiation-induced immune dysregulation

Award Number: U01AI170039
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/25/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Platelets in radiation-induced immune dysregulation - RESEARCH SUMMARY In a large-scale nuclear event, many people could be exposed to high doses of ionizing radiation (IR). This can have long-term adverse effects on immune function, putting victims at risk for immune disorders and contributing to the dysfunction of organs that depend on a functional immune system. Currently no FDA-approved drugs are available to mitigate immune dysregulation in radiation victims. The overall objectives of this project are to understand how platelets contribute to immune dysregulation after exposure to IR and to test platelet-centric countermeasures to mitigate IR-induced immune dysregulation and organ damage (specifically in the intestine and heart). Platelets can regulate immune function by binding directly to immune cells or by delivering submicron platelet-derived microparticles (PMPs) to the cells. In every healthy individual, platelets form platelet–leukocyte aggregates and generate PMPs in the circulation under normal conditions, but these activities increase under pathological conditions. Various platelet receptors interact with their specific counter receptors on leukocytes, specifically polymorphonuclear neutrophils (PMNs) and monocytes—2 crucial members of the innate immune system that can modify the adaptive immune response—to form platelet–leukocyte aggregates. Central to this interaction is platelet glycoprotein Ibα (GPIbα) binding to leukocyte Mac-1, resulting in activation of both platelets and leukocytes. PMPs can activate PMNs and monocytes by delivering cytokines, growth factors, and RNA. Notably, proteolytic cleavage of platelet GPVI is an essential step for PMP generation. Our preliminary data show that mice with dysfunctional GPIbα (cannot bind Mac-1) exhibit increased inflammation, intestinal injury, PMP generation, and lethality following a single dose of 8.5 Gy total-body irradiation (TBI) compared to wild-type mice. Moreover, we showed that mice with dysfunctional GPIbα are more prone to inflammation following polymicrobial sepsis, which can occur after IR exposure. Finally, GPVI-KO mice generate fewer PMPs and exhibit reduced plasma pro-inflammatory cytokine levels compared to mice with dysfunctional GPIbα after 8.5 Gy TBI. We hypothesize that lack of GPIbα–Mac-1 interaction and enhanced PMP generation contribute to IR-induced immune dysregulation and predict that administering exogenous GPIbα or limiting PMP generation will mitigate IR-induced immune dysregulation and organ damage. The studies outlined in this proposal will: 1) Determine whether selective blocking of GPIbα binding to Mac-1 exacerbates, while exogenous GPIbα administration mitigates, TBI-induced immune dysregulation and 2) Evaluate whether limiting PMP generation by inhibiting GPVI mitigates TBI-induced immune dysregulation. Our studies will provide insight into the previously unexplored role of platelet–leukocyte interaction and PMP generation in modulating IR-induced immune dysregulation. Most importantly, the findings will help to develop novel radiation mitigators.


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: 2025 ( Subtotal = $693,302 )
2025	2025	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Allergy and Infectious Diseases Research	000	4	6/25/2025	NON-COMPETING CONTINUATION	$693,302
														Subtotal = $693,302

Issue Date FY: 2024 ( Subtotal = $702,309 )
2024	2024	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Allergy and Infectious Diseases Research	000	3	5/7/2024	NON-COMPETING CONTINUATION	$702,309
														Subtotal = $702,309

Issue Date FY: 2023 ( Subtotal = $649,094 )
2023	2023	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Allergy and Infectious Diseases Research	000	2	5/16/2023	NON-COMPETING CONTINUATION	$649,094
														Subtotal = $649,094

Issue Date FY: 2022 ( Subtotal = $677,004 )
2022	2022	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Allergy and Infectious Diseases Research	000	1	7/25/2022	NEW	$677,004
														Subtotal = $677,004

Grand Total All Awards = $2,721,709

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Platelets in radiation-induced immune dysregulation

Award Number: U01AI170039

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 07/25/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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