Neuroinflammatin and Developmental Vulnerability to Manganese Toxicity

 描述（由申请人提供）：Tjalkens实验室（科罗拉多州立大学）最近获得了一笔赠款，用于研究在青少年发育期间必需元素锰（Mn）的过量水平如何导致神经胶质细胞的炎症激活，从而使多巴胺能神经元在以后的生活中易于损伤。该项目的数据表明，神经炎症可能是生命早期暴露于Mn和衰老期间神经功能障碍易感性增加之间的关键联系。该基金会正在使用新型转基因报告基因和基因敲除小鼠来研究这些问题，以检查调节大脑炎症的分子途径，这些分子途径增加了锰暴露个体患神经系统疾病的风险。拟议的虚拟联盟将扩展这些研究，以确定生命早期的锰暴露如何增加感染常见病毒后不良神经系统结局的风险，包括西方马脑炎病毒（WEEV），神经适应性辛德毕斯病毒和H1N1流感病毒，目前主要的大流行性流感病毒。临床和实验证据表明，病毒感染是神经退行性疾病（包括帕金森病（PD））的危险因素。嗜神经性（或神经影响性）病毒诱导PD的许多病理特征，如蛋白质聚集、氧化应激、自噬/线粒体自噬缺陷、神经炎症和黑质（SN）中的神经元损失。因此，病毒感染可能是一种重要的环境相互作用，会增加暴露于神经毒性化合物后患神经系统疾病的风险。在生命早期过度暴露于Mn不仅对神经功能具有持久影响，而且还可以在病毒感染期间增强神经炎症。这个虚拟联盟通过汇集神经病毒学（Richard Smeyne，St. Jude）和生物信息学（Ric Slayden，CSU）的有才华的新合作者来解决这个问题，以揭示Mn在暴露于常见病毒后增强与PD相关的神经变性的能力的机制。特别是H1N1流感病毒的加入，使该联盟具有高度的临床相关性，我们实验室开发的疫苗用于减轻这些模型中病毒感染的严重程度。是 我们的中心假设，即在青少年发育期间暴露于Mn将增强对WEEV和H1N1的神经效应的易感性，导致与神经胶质细胞的炎症激活相关的黑质中多巴胺能神经元的进行性丧失。该假设将通过新的特异性目的进行测试，该目的将评估Mn加剧WEEV/Sindbis（Tjalkens）或H1N1（Smeyne）感染的神经效应的能力，并使用下一代测序/RNA-Seq（Slayden）评估宿主-病原体转录组应答。因此，我们的联盟是高度响应ViCTER的计划目标，i）进行协同，跨学科的研究，ii）支持来自不同学科的个人之间的知识交流和iii）开发新的方法来理解环境化学品在疾病病因学中的作用，可能会影响临床或公共卫生实践。

 DESCRIPTION (provided by applicant): The Tjalkens lab (Colorado State University) was recently awarded a grant to examine how excessive levels of the essential element manganese (Mn) during juvenile development causes inflammatory activation of glial cells that predisposes dopaminergic neurons to injury later in life. Data from this project indicate that neuro-inflammation may be a critical link between exposure to Mn early in life and heightened susceptibility to neurological dysfunction during aging. The parent grant is exploring these questions using novel transgenic reporter and knockout mice to examine the molecular pathways regulating inflammation in the brain that increase the risk for neurological disease in Mn-exposed individuals. The proposed Virtual Consortium will extend these studies to determine how Mn exposure early in life increases the risk for adverse neurological outcomes following infection with commonly encountered viruses, including Western Equine Encephalitis virus (WEEV), neuro adapted Sindbis virus and H1N1 influenza virus, the current major pandemic flu virus. Clinical and experimental evidence implicates viral infection as a risk factor for neurodegenerative diseases, including Parkinson's disease (PD). Neurotropic (or neuro-affecting) viruses induce many of the pathological features of PD, such as protein aggregation, oxidative stress, autophagy/mitophagy defects, neuro inflammation, and neuronal loss in the substantia nigra (SN). Viral infection may therefore represent an important environmental interaction that increases the risk for neurological disease following exposure to neurotoxic compounds. Excessive exposure to Mn early in life can not only have lasting effects on neurological function but also can enhance neuro inflammation during viral infection. This Virtual Consortium addresses this question by bringing together talented new collaborators in neuro virology (Richard Smeyne, St. Jude) and bioinformatics (Ric Slayden, CSU) to uncover mechanisms underlying the capacity of Mn to enhance neurodegeneration relevant to PD following exposure to commonly encountered viruses. The addition of H1N1 influenza virus, in particular, gives this Consortium a high level of clinical relevance, as does the use of vaccine developed in our laboratory used to mitigate the severity of viral infection in these models. It is our Central Hypothesis that exposure to Mn during juvenile development will enhance susceptibility to the neurological effects of WEEV and H1N1, resulting in progressive loss of dopaminergic neurons in the substantia nigra associated with inflammatory activation of glial cells. This hypothesis will be tested by new Specific Aims that will assess the capacity of Mn to exacerbate the neurological effects of infection by either WEEV/Sindbis (Tjalkens) or H1N1 (Smeyne), with host-pathogen transcriptome responses assessed using Next Generation Sequencing/RNA-Seq (Slayden). Thus, our Consortium is highly responsive to the ViCTER programmatic goals of i) conducting synergistic, trans-disciplinary research, ii) supporting the exchange of knowledge among individuals from diverse disciplines and iii) developing novel approaches for understanding the role of environmental chemicals in the etiology of disease that could impact clinical or public health practice.