Neuroinflammatin and Developmental Vulnerability to Manganese Toxicity

神经炎症和发育对锰毒性的脆弱性

• 批准号: 9029085
• 负责人: RONALD TJALKENS
• 金额: $ 38.74万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-14 至 2017-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9029085
• 关键词: Address; Adolescent; Adult; Affect; Aging; Arboviruses; Attenuated; Autophagocytosis; Award; Bioinformatics; Bioluminescence; Brain; Cell Death; Cells; Child; Clinical; Colorado; Data; Defect; Development; Discipline; Disease; Disease Progression; Elements; Environmental Risk Factor; Etiology; Exposure to; Flu virus; General Population; Goals; Grant; Immune; Immunotherapy; In Situ; In Vitro; Incidence; Individual; Infection; Inflammation; Inflammatory; Influenza; Influenza A Virus, H1N1 Subtype; Injury; Knock-out; Knockout Mice; Knowledge; Laboratories; Life; Link; Longevity; Luciferases; Manganese; Mediating; Metals; Modeling; Molecular; Mus; Nerve Degeneration; Nervous System Physiology; Nervous System Trauma; Neurodegenerative Disorders; Neuroglia; Neurologic; Neurologic Dysfunctions; Neurological outcome; Neuronal Injury; Neurons; Neurotoxins; Neurovirology; Outcome; Oxidative Stress; Parkinson Disease; Parkinsonian Disorders; Pathway interactions; Phenotype; Population; Predisposition; Public Health; Public Health Practice; Qualifying; RNA Viruses; Regulator Genes; Reporter; Research; Risk; Risk Factors; Role; Saint Jude Children' s Research Hospital; Satellite Viruses; Severities; Signal Transduction; Sindbis Virus; Substantia nigra structure; Testing; Toxic effect; Transgenic Organisms; Universities; Vaccines; Viral; Virus; Virus Diseases; Western Equine Encephalitis Virus; Work; base; brain tissue; clinically relevant; dopaminergic neuron; drinking water; environmental chemical; experience; gene environment interaction; glial activation; improved; influenzavirus; interest; meetings; nervous system disorder; neuroinflammation; neuron loss; neurotoxic; neurotropic; neurotropic virus; next generation sequencing; novel; novel strategies; pandemic disease; pandemic influenza; parent grant; pathogen; protein aggregation; public health relevance; response; soy; tool; transcriptome; transcriptome sequencing; transcriptomics; virology; virtual

 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.

 描述（由申请人提供）：Tjalkens 实验室（科罗拉多州立大学）最近获得了一笔拨款，用于研究幼体发育过程中必需元素锰 (Mn) 水平过高如何导致神经胶质细胞炎症激活，从而使多巴胺能神经元在以后的生活中容易受到损伤。该项目的数据表明，神经炎症可能是生命早期接触锰与衰老过程中神经功能障碍的易感性增加之间的关键联系。母基金正在利用新型转基因报告基因和基因敲除小鼠来探索这些问题，以检查调节大脑炎症的分子途径，这些炎症会增加接触锰的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，以确定生命早期接触锰如何增加感染常见病毒（包括西方马脑炎病毒（WEEV）、神经适应性辛德比斯病毒和当前主要大流行流感病毒 H1N1 流感病毒）后出现不良神经结果的风险。临床和实验证据表明病毒感染是神经退行性疾病的危险因素，包括帕金森病 (PD)。亲神经（或影响神经）病毒可诱发 PD 的许多病理特征，例如蛋白质聚集、氧化应激、自噬/线粒体自噬缺陷、神经炎症和黑质 (SN) 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，会增加接触神经毒性化合物后患神经系统疾病的风险。生命早期过量接触锰不仅会对神经功能产生持久影响，还会增强病毒感染期间的神经炎症。该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，科罗拉多州立大学）方面才华横溢的新合作者来解决这个问题，以揭示 Mn 增强暴露于常见病毒后与 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也是如此。这是 我们的中心假设是，幼体发育期间接触锰会增强对 WEEV 和 H1N1 神经系统影响的敏感性，导致黑质中与神经胶质细胞炎症激活相关的多巴胺能神经元逐渐丧失。这一假设将通过新的特定目标进行测试，该目标将评估锰加剧 WEEV/Sindbis (Tjalkens) 或 H1N1 (Smeyne) 感染的神经系统影响的能力，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 计划目标：i) 开展协同、跨学科研究，ii) 支持不同学科的个人之间的知识交流，以及 iii) 开发新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病因学中的作用。