CMA: Immune/inflammatory priming in exacerbating responses to GWVI stressors: implications for GWVI treatments

CMA：免疫/炎症引发加剧对 GWVI 应激源的反应：对 GWVI 治疗的影响

• 批准号: 10266035
• 负责人: Giulio Maria Pasinetti
• 金额: --
• 依托单位: JAMES J PETERS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10266035
• 关键词: Animal Model; Attenuated; Autoimmune Diseases; Award; Biological Availability; Biological Models; Brain; Brain Pathology; Bromine; Chemistry; Clinical; Collaborations; Complex; Diagnosis; Disease; Etiology; Event; Experimental Models; Exposure to; Fatigue; Future; Genetic Polymorphism; Genetic Transcription; Genetic Variation; Goals; Gulf War; Gulf War veteran; Health Promotion; Immune; Immune response; Immune system; Immunity; Immunologic Tests; Immunologics; Immunotherapeutic agent; Impaired cognition; Individual; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Interdisciplinary Study; Interleukin-1 beta; Intervention; Joints; Knock-out; Lead; Link; Mediating; Medical center; Mental Depression; Methods; Microbiology; Microglia; Modeling; Molecular; Mood Disorders; Mus; Neuroimmune system; Neurosciences; Organ failure; Outcome Study; Pain; Pathologic; Pathology; Pathway interactions; Peripheral; Permethrin; Pesticides; Pharmacologic Substance; Pharmacology; Phenotype; Plasma; Probiotics; Process; Proteins; Psychological Stress; Public Health Schools; Quality of life; Reaction; Research; Research Personnel; Research Project Grants; Risk; Risk Factors; Role; Science; Stimulus; Stress; Symptoms; Testing; Therapeutic; Toxic Environmental Substances; Toxin; Translating; Translations; Tumor-infiltrating immune cells; Uranium; Vaccination; Vaccines; Veterans; Veterans Health Administration; Vision; Work; arm; base; cytokine; design; experimental study; fluorophosphate; gut dysbiosis; immune activation; improved; inhibitor/antagonist; innovation; insight; interest; mRNA Expression; mouse model; multidisciplinary; neuroinflammation; novel; novel strategies; novel therapeutic intervention; novel therapeutics; pre-clinical; pre-clinical research; programs; psychological stressor; pyridostigmine; response; social defeat; stressor; therapeutic target; tissue degeneration; translational study

Project Summary/Abstract This Collaborative Merit Review Award for Research (I01) proposed in response to RFA BX-18-007 from the Veteran Health Administration is a joint effort by investigators from the JJ Peters VA Medical Center (Bronx, NY) Project 1, Arnold School of Public Health and Wm Jennings Bryan Dorn VA Medical Center (Columbia, SC) Project 2, Brain Science Center VA Medical Center (Minneapolis, MN) Project 3. We define a vision for an integrated and multidisciplinary program of preclinical research projects all linked by the ultimate goal to better characterize the mechanism of persistent and aberrant immunological activity in Gulf War Veteran Illnesses (GWVI) by developing experimental model systems, with the ultimate goal of developing novel therapeutic interventions. Gulf War Veterans’ Illnesses is a multifaceted disorder characterized by a range of symptoms including cognitive impairment, fatigue, pain, mood disorders, among others. Recent evidence suggests that the onset and progression of these symptoms may be the result of disequilibrium in these subjects’ immune systems. During deployment GWV were exposed to a unique variety of toxic agents that were specific to the Gulf War theatre, such as pyridostigmine bromine (PB), diisopropyl fluorophosphates (DFP), permethrin, and depleted uranium which current evidence indicates lowered thresholds to immunological responses and resulted in the persistent and heightened activity of certain arms of the immune system; a phenomenon best described as “immunological priming”. In addition, they received more than 20 vaccines that could have overloaded the immune system. In support of these considerations, subjects with GWVI often have shown pathological signatures in common with autoimmune disorders and generalized inflammatory disorders, such as increased plasma concentrations of pro-inflammatory cytokines, unspecific tissue degeneration, and organ failure. Based on this concept, the three proposed collaborative research projects were designed to better understand how primed immune systems may contribute to GWVI- type phenotypes by exploring how multiple GWI conditions recapitulated in animal models may synergize and eventually provide new mechanistic evidence for translation studies. For example, Project 2 was designed to understand how GW toxin induced gut inflammasome activation causes gut dysbiosis and may lead to persistent or heightened immune-inflammatory responses and GWVI symptoms. As the goal of Project 3 is designed the hypothesis that lack of specific immunity leads to vaccine-induced inflammatory reaction in the brain, Project 2 will collaborate with project 3 to test the contribution of inflammasome priming and genetic diversity to gut dysbiosis and persistent immunological responses. Similarly, Project 1, which is designed to test how immunological priming may heighten inflammatory responses to psychological stressors, will collaborate with project 2 and project 3 by exploring how the NLRP3 inflammasome may contribute to heightened inflammation induced by gut dysbiosis or HLA polymorphisms, respectively. The outcome of these studies is of great interest not only because this will establish a novel link between inflammasome priming, genetic diversity and gut-dysbiosis toxemic response, but it will also provide insight to test novel therapeutic approaches that target the persistent activation of the immune system, either using immunotherapeutic approaches against vaccine toxins, probiotics to attenuate gut dysbiosis. Our proposed studies are innovative in terms of their scope, since it will fill the fundamental gaps needed for future translational studies. Most importantly our multiscale technological innovative approaches, which include knockout murine models of GWVI, including for the HLA and NLRP3 proteins, will enable our interdisciplinary research team with outstanding expertise in neuroscience, pharmacology, microbiology, chemistry to thoroughly investigate the molecular mechanisms underlying the etiology of GWVI.

项目概要/摘要 这项合作研究优异评审奖 (I01) 是为了回应 RFA BX-18-007 而提出的 退伍军人健康管理局是 JJ Peters VA 医疗中心（布朗克斯、 纽约）项目 1，阿诺德公共卫生学院和 Wm Jennings Bryan Dorn VA 医疗中心（哥伦比亚， SC) 项目 2，脑科学中心 VA 医疗中心（明尼苏达州明尼阿波利斯）项目 3。我们定义了一个愿景 临床前研究项目的综合和多学科计划，所有这些项目都与最终目标联系在一起 更好地表征海湾战争退伍军人持续和异常免疫活性的机制 通过开发实验模型系统来研究疾病（GWVI），最终目标是开发新颖的 治疗干预。海湾战争退伍军人疾病是一种多方面的疾病，其特征是一系列 症状包括认知障碍、疲劳、疼痛、情绪障碍等。最近的证据 表明这些症状的发生和进展可能是这些因素不平衡的结果 受试者的免疫系统。在部署期间，GWV 暴露于多种独特的有毒物质， 海湾战争战场特有的药物，如溴吡斯的明 (PB)、二异丙基氟磷酸盐 （DFP）、氯菊酯和贫铀，目前的证据表明阈值降低 免疫反应并导致某些免疫臂的持续和增强的活性 系统;这种现象最好被描述为“免疫启动”。此外，他们还收到了20多个 可能导致免疫系统超负荷的疫苗。为了支持这些考虑，受试者 GWVI 通常表现出与自身免疫性疾病相同的病理特征，并且具有广泛性 炎症性疾病，例如促炎细胞因子的血浆浓度升高，非特异性 组织退化和器官衰竭。基于这一理念，三人提出了合作研究 项目旨在更好地了解免疫系统如何促进 GWVI 型 通过探索动物模型中重现的多种 GWI 条件如何协同作用和 最终为翻译研究提供新的机制证据。例如，项目 2 的设计目的是 了解 GW 毒素诱导肠道炎症小体激活如何导致肠道菌群失调，并可能导致 持续或增强的免疫炎症反应和 GWVI 症状。由于项目 3 的目标是 设计了这样的假设：缺乏特异性免疫会导致疫苗诱导的炎症反应 大脑，项目 2 将与项目 3 合作，测试炎症体启动和遗传的贡献 肠道菌群失调和持续免疫反应的多样性。同样，项目 1 的目的是 测试免疫启动如何增强对心理压力源的炎症反应，将 与项目 2 和项目 3 合作，探索 NLRP3 炎症小体如何促进 分别由肠道菌群失调或 HLA 多态性引起的炎症加剧。结果 这些研究非常有趣，不仅因为这将在炎症小体之间建立新的联系 启动、遗传多样性和肠道生态失调毒血症反应，但它也将为测试新的 针对免疫系统持续激活的治疗方法，或者使用 针对疫苗毒素和益生菌的免疫治疗方法可减轻肠道菌群失调。我们提出的 研究范围具有创新性，因为它将填补未来所需的基本空白 转化研究。最重要的是我们的多尺度技术创新方法，其中包括 GWVI 的敲除小鼠模型，包括 HLA 和 NLRP3 蛋白，将使我们的跨学科研究成为可能 研究团队在神经科学、药理学、微生物学、化学领域拥有杰出的专业知识 深入研究 GWVI 病因学的分子机制。