Platelets in radiation-induced immune dysregulation

辐射引起的免疫失调中的血小板

• 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
• 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

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.

研究概要 在大规模核事件中，许多人可能会受到高剂量的电离辐射 (IR)。 对免疫功能产生长期不利影响，受害者面临免疫紊乱的风险，并导致 目前还没有 FDA 批准的药物来治疗依赖功能性免疫系统的器官功能障碍。 可用于减轻辐射受害者的免疫失调 该项目的总体目标是 了解暴露于红外线后血小板如何导致免疫失调并测试以血小板为中心的 减轻红外线引起的免疫失调和器官损伤（特别是肠道）的对策 血小板可以通过直接结合免疫细胞或通过传递亚微米来调节免疫功能。 在每个健康个体中，血小板形成血小板-白细胞。 在正常情况下，这些活动会在循环中聚集并产生 PMP，但在以下情况下这些活动会增加： 各种血小板受体与白细胞上的特定反受体相互作用， 特别是多形核中性粒细胞 (PMN) 和单核细胞——先天免疫的两个重要成员 可以改变适应性免疫反应的系统——形成血小板-白细胞聚集体，这是这一过程的核心。 相互作用是血小板糖蛋白 Ibα (GPIbα) 与白细胞 Mac-1 结合，导致两个血小板均被激活 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，我们的初步数据显示，血小板 GPVI 的蛋白水解是 PMP 生成的重要步骤。 GPIbα 功能失调（无法结合 Mac-1）的小鼠表现出炎症、肠道损伤、PMP 增加 与野生型小鼠相比，单剂量 8.5 Gy 全身照射 (TBI) 后的产生和致死率。 此外，我们发现，GPIbα 功能失调的小鼠在多种微生物感染后更容易出现炎症。 最后，GPVI-KO 小鼠产生较少的 PMP，并且表现出减少。 8.5 Gy TBI 后与具有功能性 GPIbα 的小鼠相比，血浆促炎细胞因子水平。 研究发现，缺乏 GPIbα-Mac-1 相互作用和增强的 PMP 生成有助于 IR 诱导 免疫失调并预测施用外源性 GPIbα 或限制 PMP 的产生将缓解 本提案中概述的研究将： 1) 确定 IR 引起的免疫失调和器官损伤。 当外源性 GPIbα 给药时，选择性阻断 GPIbα 与 Mac-1 的结合是否会加剧 减轻 TBI 引起的免疫失调，2) 评估是否通过抑制来限制 PMP 的产生 GPVI 可减轻 TBI 引起的免疫失调。 血小板-白细胞相互作用和 PMP 生成在调节 IR 诱导免疫中的尚未探索的作用 最重要的是，这些发现将有助于开发新型辐射缓解剂。