Encephalitic viral infection and susceptibility to dopaminergic neurotoxins

脑炎病毒感染和对多巴胺能神经毒素的易感性

基本信息

批准号：
10240481
负责人：
RONALD TJALKENS
金额：
$ 60.35万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-20 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10240481
关键词：
Address Affect Age Aging Alzheimer&apos s Disease Animal Model Area Astrocytes Bacteria Basic Science Brain region Clinical Clinical Markers Colorado Development Disease Dose Environmental Exposure Environmental Risk Factor Etiology Event Experimental Models Exposure to General Population Genetic Geography Goals Heavy Metals Incidence Individual Infection Inflammation Inflammatory Influenza A Virus, H1N1 Subtype Injury Knockout Mice Knowledge La Crosse virus Laboratories Link Manganese Medical Metals Microglia Modeling Molecular Motor Movement Disorder Society Unified Parkinson&apos s Disease Rating Scale Mus NF-kappa B Nerve Degeneration Nervous System Trauma Neuraxis Neurodegenerative Disorders Neuroglia Neuroimmune Neurologic Dysfunctions Neurological outcome Neurology Neuronal Injury Neurons Neurotoxins Neurovirology Occupational Exposure Outcome Study Parkinson Disease Pathologic Patients Pattern Peripheral Pesticides Phenotype Policies Population Positron-Emission Tomography Predisposition Prevention Public Health Public Health Practice RNA Viruses Recording of previous events Risk Rotenone Serology Severities Signal Pathway Signal Transduction Structure Testing Transgenic Mice Universities Viral Virus Virus Diseases Washington West Nile virus Western Equine Encephalitis Virus basal ganglia injury base clinical imaging environmental agent environmental stressor gene environment interaction glial activation imaging study improved in vivo influenzavirus interdisciplinary approach interest medical schools mouse model nervous system disorder neuroimaging neuroinflammation neurotoxic neurotropic virus pandemic influenza patient population pre-formed fibril protein aggregation public health intervention response theories virtual

项目摘要

Project Summary The overall focus of this Virtual Consortium project is on neuroinflammation and the neuro-immune axis as a critical link between viral infection and susceptibility to injury from environmental neurotoxins. Neuroinflammatory activation of glial cells may represent an important causal link in the `two-hit' theory of neurological disease, sensitizing susceptible brain regions to damage from distinct environmental stressors and thereby promoting the onset of clinical disease. The proposed Virtual Consortium will examine how infection with commonly encountered RNA viruses, including Western Equine Encephalitis virus (WEEV) and H1N1 influenza virus, the current worldwide pandemic flu virus, influences the severity of neurological outcomes following exposure to neurotoxic metals and pesticides. Neuroinflammatory mechanisms examined in animal models will be compared to advanced PET imaging of neuroinflammation in individuals occupationally exposed to manganese (Mn) in conjunction with an analysis of their history of viral exposure. This Virtual Consortium will examine signaling mechanisms in microglia and astrocytes that regulate neuroinflammatory injury following exposure to viruses and selected environmental neurotoxins using both transgenic mouse models as well as clinical imaging in Mn- exposed patients. The Consortium will bring together collaborators in neurovirology and neurodegeneration (Richard Smeyne, Thomas Jefferson University), neurology and clinical imaging (Brad Racette, Washington University, St. Louis) and neuroinflammation (Ronald Tjalkens, Colorado State University) to identify key neuroinflammatory mechanisms modulating the response to infectious and neurotoxic environmental exposures that could increase the risk of developing neurodegenerative disease. It is our central hypothesis that encephalitic viral infection causes a persistent inflammatory phenotype in microglia and astrocytes that enhances susceptibility to neurotoxic injury. This hypothesis will be tested by the following interconnected Specific Aims: Specific Aim 1 (Tjalkens, Colorado State University) - Identify inflammatory signaling pathways in microglia modulated by Western Equine Encephalitis Virus (WEEV) that promote glial activation and neuronal injury from manganese and rotenone; Specific Aim 2 (Smeyne, Thomas Jefferson University) - Determine mechanisms by which H1N1 influenza virus alters the effects of manganese and rotenone on neuronal injury; Specific Aim 3 (Racette, Washington University School of Medicine) - Characterize patterns of neurological dysfunction and microglial activation in manganese (Mn) exposed workers. We expect that this Virtual Consortium will have a significant impact on our understanding of interactions between environmental neurotoxins and viruses that can promote neurological disease, which are currently only poorly understood. Such interactions are likely to have enormous implications to public health, given the widespread incidence of both viral infections and exposure to neurotoxic agents in the general population. The proposed ViCTER consortium addresses this problem with an interdisciplinary approach integrating powerful basic research models with advanced PET neuroimaging in a patient population occupationally exposed to Mn that will be examined for a history of viral infections. The outcomes from these studies are very likely to inform better policy decisions regarding identification and prevention of environmental risk factors for neurodegenerative disease.

项目摘要这个虚拟财团项目的总体重点是神经炎症和神经免疫轴作为一个病毒感染与对环境神经毒素受伤的敏感性之间的关键联系。神经炎症神经胶质细胞的激活可能代表着神经系统疾病的“两击”理论中的重要因果关系，敏感易感大脑区域对不同的环境压力源损害，从而促进临床疾病的发作。拟议的虚拟财团将检查通常如何感染遇到了RNA病毒，包括西马脑炎病毒（WEEV）和H1N1流感病毒，当前全球大流血病毒影响了暴露后神经系统结局的严重程度神经毒性金属和农药。将比较在动物模型中检查的神经炎症机制在职业暴露于锰（MN）的个体中神经炎症的高级宠物成像结合其病毒暴露史的分析。这个虚拟财团将检查信号传导暴露于病毒后调节神经炎性损伤的小胶质细胞和星形胶质细胞的机制并使用两种转基因小鼠模型以及Mn-中的临床成像进行选择的环境神经毒素暴露的患者。该财团将汇集神经病毒学和神经变性的合作者（理查德·史密斯（Richard Smeyne），托马斯·杰斐逊大学（Thomas Jefferson University 大学，圣路易斯）和神经炎症（科罗拉多州立大学的罗纳德·塔尔孔斯），以识别关键神经炎症机制调节对感染和神经毒性环境暴露的反应这可能会增加发展神经退行性疾病的风险。我们的中心假设是脑病病毒感染引起小胶质细胞和星形胶质细胞中持续的炎症表型，从而增强对神经毒性损伤的敏感性。该假设将通过以下相互联系的特定目的来检验：特定目的1（科罗拉多州立大学Tjalkens） - 识别小胶质细胞中的炎症信号通路由西马脑炎病毒（WEEV）调节，该病毒促进神经胶质激活和神经元损伤锰和烤面包酮；特定目标2（Smeyne，Thomas Jefferson University） - 确定机制 H1N1流感病毒会改变锰和鱼藤酮对神经元损伤的影响；具体目标3 （华盛顿大学医学院） - 神经功能障碍和锰（MN）暴露的工人中的小胶质细胞激活。我们希望这个虚拟财团将有一个对我们对环境神经毒素与病毒之间相互作用的理解的重大影响促进神经系统疾病，目前仅了解的神经疾病。这样的互动可能有鉴于病毒感染的广泛发病率和暴露于公共卫生的巨大影响普通人群中的神经毒性剂。拟议的Victer财团通过跨学科方法将强大的基础研究模型与高级PET神经影像整合在一起患者人口职业暴露于MN，将检查病毒感染史。这这些研究的结果很可能会为有关识别和预防神经退行性疾病的环境危险因素。