Encephalitic viral infection and susceptibility to dopaminergic neurotoxins

项目摘要 这个虚拟联盟项目的总体重点是神经炎症和神经免疫轴作为 病毒感染与环境神经毒素损伤易感性之间的关键联系。神经炎性 神经胶质细胞的激活可能是神经疾病“两次打击”理论中的一个重要因果联系。 使敏感的大脑区域对不同环境应激源造成的损伤敏感，从而促进 临床疾病的发病。拟议的虚拟联盟将审查感染通常 遇到的RNA病毒，包括西部马脑炎病毒(Weev)和H1N1流感病毒， 目前世界范围内的大流行性流感病毒，影响暴露于 神经毒性金属和杀虫剂。将比较在动物模型中检验的神经炎性机制 对职业性接触锰(Mn)个体的神经炎症进行先进的PET成像 结合对他们的病毒接触史的分析。该虚拟联盟将检查信令 小胶质细胞和星形胶质细胞调节病毒暴露后神经炎性损伤的机制 并利用转基因小鼠模型和临床成像对环境神经毒素进行了筛选。 暴露的病人。该联盟将汇集神经病毒学和神经退行性变方面的合作者 (理查德·斯迈恩，托马斯·杰斐逊大学)，神经学和临床成像(布拉德·拉塞特，华盛顿 和神经炎症(科罗拉多州立大学的Ronald Tjalkens)来确定关键 调节对感染性和神经毒性环境暴露反应的神经炎性机制 这可能会增加患神经退行性疾病的风险。我们的中心假设是 脑炎病毒感染导致小胶质细胞和星形胶质细胞持续的炎性表型 对神经毒性损伤的敏感性。这一假设将通过以下相互关联的具体目标来检验： 特定目标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 受西方马脑炎病毒(Weev)调控，促进神经胶质细胞激活和神经元损伤 锰和鱼藤酮；特定目标2(Smeyne，Thomas Jefferson University)--通过 哪种H1N1流感病毒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)-描述神经功能障碍的模式和 锰作业工人的小胶质细胞活化。我们预计这个虚拟联盟将有一个 对我们理解环境神经毒素和病毒之间的相互作用产生了重大影响 促进神经系统疾病，目前人们对此知之甚少。这样的互动很可能会有 对公众健康的巨大影响，因为病毒感染和暴露于 普通人群中的神经毒剂。提议的Victer财团通过一个 将强大的基础研究模型与先进的PET神经成像相结合的跨学科方法 职业暴露于MN的患者群体，将接受病毒感染史检查。这个 这些研究的结果很可能为更好的识别和决策提供依据 预防神经退行性疾病的环境危险因素。

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.