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: 10752604
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10752604
• 关键词: Animal Model; Attenuated; Autoimmune Diseases; Award; Biological Availability; Biological Models; Brain; Brain Pathology; Bromine; Chemistry; Clinical; Collaborations; Complex; Diagnosis; Disease; Education; 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; 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; Pharmacology; Phenotype; Plasma; Predisposition; Probiotics; Process; Proteins; Psychological Stress; Public Health Schools; Quality of life; Reaction; Research; Research Personnel; Research Project Grants; Risk; Risk Factors; Role; Science; Septic Toxemia; Stimulus; Stress; Symptoms; Testing; Therapeutic; Toxic Environmental Substances; Toxin; Translating; Uranium; Vaccination; Vaccines; Veterans; Veterans Health Administration; Vision; Work; arm; cytokine; design; experimental study; fluorophosphate; gut dysbiosis; immune activation; immune cell infiltrate; improved; inhibitor; innovation; innovative technologies; insight; interest; mRNA Expression; mouse model; multidisciplinary; neuroinflammation; novel; novel strategies; novel therapeutic intervention; novel therapeutics; pharmacologic; pre-clinical; pre-clinical research; programs; psychological stressor; pyridostigmine; response; social defeat; stressor; synergism; 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.

项目总结/摘要 该研究合作优秀评审奖（I 01）是为了响应来自 退伍军人健康管理局是由JJ彼得斯退伍军人医疗中心（布朗克斯， 纽约）项目1，阿诺德公共卫生学院和Wm詹宁斯布赖恩多恩VA医疗中心（哥伦比亚， SC）项目2，脑科学中心VA医学中心（明尼阿波利斯，MN）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相关联， 更好地描述海湾战争退伍军人中持续和异常免疫活性的机制 疾病（GWVI）通过开发实验模型系统，最终目标是开发新的 治疗干预。海湾战争退伍军人疾病是一种多方面的疾病，其特点是一系列的 症状包括认知障碍、疲劳、疼痛、情绪障碍等。最近的证据 提示这些症状的发生和发展可能是这些疾病的不平衡的结果。 实验对象的免疫系统在部署期间，GWV暴露于各种独特的有毒物质， 是海湾战场特有的，如溴吡啶斯的明（PB），二异丙基氟磷酸盐 (DFP)目前的证据表明， 免疫反应，并导致持续和提高活动的某些武器的免疫 系统;最好描述为“免疫启动”的现象。此外，他们还收到了20多份 疫苗可能会使免疫系统过载。为了支持这些考虑， GWVI通常显示出与自身免疫性疾病和全身性免疫性疾病共同的病理特征。 炎症性疾病，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的设想 这些项目旨在更好地了解引发免疫系统如何有助于GWVI型 通过探索在动物模型中重现的多种GWI条件如何协同作用， 为翻译研究提供了新的机制依据。例如，项目2旨在 了解GW毒素诱导的肠道炎性体激活如何导致肠道生态失调，并可能导致 持续或增强的免疫炎症反应和GWVI症状。项目3的目标是 设计了一个假设，即缺乏特异性免疫导致疫苗诱导的炎症反应， 大脑，项目2将与项目3合作测试炎性小体启动和遗传的贡献 多样性导致肠道生态失调和持续的免疫反应。同样，项目1旨在 测试如何免疫启动可能会提高炎症反应的心理压力，将 与项目2和项目3合作，探索NLRP 3炎性小体如何有助于 分别由肠道生态失调或HLA多态性诱导的炎症增强。的结果 这些研究引起了极大的兴趣，不仅因为这将建立炎性小体与 启动，遗传多样性和肠道生态失调毒血症反应，但它也将提供洞察力，以测试新的 靶向免疫系统持续激活的治疗方法， 免疫方法对抗疫苗毒素，益生菌减弱肠道生态失调。我们提出的 研究在范围上是创新的，因为它将填补未来所需的根本空白。 翻译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NLRP 3蛋白，将使我们的跨学科 研究团队在神经科学，药理学，微生物学，化学， 深入研究GWVI病因的分子机制。