Platelets in radiation-induced immune dysregulation

辐射引起的免疫失调中的血小板

基本信息

批准号：
10474901
负责人：
Martin J Cannon
金额：
$ 67.7万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-25 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10474901
关键词：
Acute Address Adverse effects Age Antibodies Area Autoimmune Diseases B-Lymphocytes Binding Biological Blood Circulation Blood Platelets Bone Marrow CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cardiovascular Diseases Cell physiology Cells Data Dendritic Cells Development Dose Event Exhibits Experimental Models Exposure to FDA approved Functional disorder Generations Glycoproteins Growth Factor Health Heart Histology Hour Human IL2RA gene ITGAM gene ITGAX gene Immune Immune System Diseases Immune system Immunosuppression In Vitro Incubated Individual Inflammation Inflammatory Innate Immune System Interleukin 4 Receptor Intestines Ionizing radiation Knockout Mice Leukocytes Ligand Binding Domain Macrophage-1 Antigen Mus N-terminal Nuclear Accidents Organ Pathologic Persons Pharmaceutical Preparations Phenotype Plasma Platelet Activation Platelet Glycoproteins Play Production RNA Radiation Radiation Accidents Radiation Injuries Radiation Protection Radiation exposure Radiation induced damage Regulation Regulatory T-Lymphocyte Research Risk Role Serum Spleen Testing Vaccination Whole-Body Irradiation Wild Type Mouse adaptive immune response bone cell cytokine gastrointestinal heart function immune function immunoregulation in vivo insight intestinal injury leukocyte activation macrophage medical countermeasure member monocyte morphometry mouse model mutant mouse model neutrophil novel organ injury polymicrobial sepsis primary endpoint radiation mitigator radiological attack receptor response secondary endpoint small molecule submicron systemic inflammatory response

项目摘要

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.

研究摘要在一个大规模的核事件中，许多人可能会暴露于高剂量的电离辐射（IR）。这可以对免疫功能产生长期不良影响，使免疫疾病吓坏取决于功能免疫系统的器官功能障碍。目前尚无FDA批准的药物可用于减轻辐射可怕的免疫失调。该项目的总体目标是了解血小板暴露于IR后如何促进免疫失调并测试以血小板为中心相反，以减轻IR诱导的免疫失调和器官损伤（特别是在肠道中和心）。血小板可以通过直接与免疫细胞结合或传递亚微米来调节免疫功能细胞的血小板衍生的微粒（PMP）。在每个健康的个体中，血小板形成血小板 - leukocyte 在正常情况下，在循环中汇总并生成PMP，但这些活动在病理状况。各种血小板受体与白细胞上的特定计数受体相互作用，特异性多形核中性粒细胞（PMN）和单核细胞 - 2个先天免疫的至关重要成员可以修改适应性免疫响应的系统 - 形成血小板 - 白细胞聚集体。核心相互作用是与白细胞MAC-1结合的血小板糖蛋白IBα（GPIBα），导致两个血小板的激活和白细胞。 PMP可以通过传递细胞因子，生长因子和RNA来激活PMN和单核细胞。值得注意的是，血小板GPVI的蛋白水解切割是PMP生成的重要步骤。我们的初步数据显示那个患有功能障碍GPIBα（无法结合MAC-1）的小鼠暴露于感染增加，肠损伤，PMP 与野生型小鼠相比，单剂量为8.5 Gy总体体照射（TBI）后产生和致死性。此外，我们证明了功能障碍GPIBα的小鼠在多肌动物后更容易发生炎症败血症，可能在IR暴露后发生。最后，GPVI-KO小鼠产生的PMP较少，暴露于降低与8.5 Gy TBI后功能失调的GPIBα的小鼠相比，血浆促炎性细胞因子水平相比。我们假设缺乏GPIBα-MAC-1相互作用和增强的PMP产生有助于IR诱导免疫失调并预测给施用外源GPIBα或限制PMP的生成会减轻 IR诱导的免疫失调和器官损伤。该提案中概述的研究将：1）确定 GPIBα与MAC-1的结合是否有选择性阻断，而外源GPIBα给药减轻TBI诱导的免疫失调，2）评估是否通过抑制限制PMP的生成 GPVI减轻TBI诱导的免疫失调。我们的研究将提供有关以前的见解血小板 - 白细胞相互作用和PMP产生的意外作用在调节IR诱导的免疫失调。最重要的是，这些发现将有助于开发新型的辐射缓解剂。