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)最近获得了一项拨款，旨在研究幼年发育过程中必需元素锰(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命中容易受到损伤。来自该项目的数据表明，神经炎症可能是生命早期暴露于锰与衰老过程中神经功能障碍易感性增加之间的关键联系。家长基金正在探索这些问题，使用新的转基因报告和基因敲除小鼠来检查调节大脑炎症的分子通路，这些分子通路增加了接触锰的个人患神经疾病的风险。拟议的虚拟联盟将扩展这些研究，以确定生命早期接触锰如何增加感染常见病毒后出现不良神经后果的风险，这些病毒包括西马脑炎病毒(Weev)、神经适应的辛德比斯病毒和目前主要的大流行流感病毒H1N1流感病毒。临床和实验证据表明，病毒感染是包括帕金森病(PD)在内的神经退行性疾病的风险因素。嗜神经性(或影响神经)病毒导致PD的许多病理特征，如蛋白质聚集、氧化应激、自噬/有丝分裂吞噬缺陷、神经炎症和黑质(SN)神经元丢失。因此，病毒感染可能是一种重要的环境相互作用，它增加了暴露于神经毒性化合物后患神经疾病的风险。生命早期过量接触锰不仅会对神经功能产生持久的影响，还会在病毒感染期间加剧神经炎症。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，以揭示在暴露于常见病毒后，MN增强与PD相关的神经退化的潜在机制。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，在这些模型中，使用我们实验室开发的疫苗来减轻病毒感染的严重性也是如此。它是 我们的中心假设是，在幼年发育期间暴露于锰将增强对Weev和H1N1病毒的神经效应的敏感性，导致黑质多巴胺能神经元的进行性丧失，与胶质细胞的炎性激活有关。这一假说将通过新的特定目标进行验证，这些目标将评估MN加剧Weev/Sindbis(Tjalkens)或H1N1(Smeyne)感染的神经影响的能力，并使用下一代测序/RNA-Seq(Slayden)评估宿主-病原体转录组反应。因此，我们的联盟高度响应Victer的计划目标，即i)进行协同的、跨学科的研究，ii)支持不同学科的个人之间的知识交流，iii)开发新的方法来了解环境化学品在可能影响临床或公共卫生实践的疾病的病因学中的作用。

 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.