U01AI170039

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 - two 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.

Preliminary data shows 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, it is shown 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.

The hypothesis is that lack of GPIbα-Mac-1 interaction and enhanced PMP generation contribute to IR-induced immune dysregulation, and it is predicted 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.
2) Evaluate whether limiting PMP generation by inhibiting GPVI mitigates TBI-induced immune dysregulation.

These 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.

University Of Arkansas For Medical Sciences

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93.310 - Trans-NIH Research Support

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Little Rock, Arkansas 722057101 United States

Single Zip Code

Radiation-Induced Immune Dysfunction (U01 Clinical Trial Not Allowed) (RFA-AI-21-019)

Amendment Since initial award the total obligations have increased 302% from $677,004 to $2,721,709.