Neuroinflammatin and Developmental Vulnerability to Manganese Toxicity

神经炎症和发育对锰毒性的脆弱性

基本信息

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
项目类别：
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&apos 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

项目摘要

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（由适用提供）：最近授予了Tjalkens Lab（科罗拉多州立大学）的赠款，以检查如何超过少年发育期间的基本元素锰（MN）水平，从而导致神经胶质细胞的炎症激活，使多巴胺能神经元在以后的生活中受伤。该项目的数据表明，神经炎症可能是生命早期接触MN的关键联系，而在衰老期间对神经功能障碍的敏感性提高。父母赠款正在使用新型的转基因报告基因和基因敲除小鼠探索这些问题，以检查大脑中的分子途径调节感染，从而增加了暴露于MN的个体中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MN在生命早期暴露在感染通常遇到的病毒后的不良神经系统结局的风险，包括西部马脑炎病毒（WEEV），Neuro compoppated sindbis病毒和H1N1适应于当前的主要流血病毒。临床和实验证据意味着病毒感染是神经退行性疾病的危险因素，包括帕金森氏病（PD）。神经性（或神经作用）病毒影响PD的许多病理特征，例如蛋白质聚集，氧化应激，自噬/线粒体缺陷，神经炎症和神经元损失，而Nigra（SN）（SN）。因此，病毒感染可能代表着一种重要的环境相互作用，该环境相互作用增加了暴露于神经毒性化合物后神经系统疾病的风险。过度接触MN生命的早期不仅会对神经功能产生持久影响，而且可以增强病毒感染期间神经炎症。这个虚拟的联盟通过将有才华的新合作者汇总到Neuro病毒学（Richard Smeyne，St.Jude）和生物信息学（Ric Slayden，CSU）中，以发现MN的能力增强与普通病毒相关的PD相关的MN能力的机制来解决这个问题。尤其是H1N1影响病毒的添加使该财团具有高水平的临床相关性，在我们的实验室中开发的疫苗的使用也一样，用于减轻这些模型中病毒感染的严重性。这是我们的核心假设是，在少年发育过程中暴露于MN将增强对WEEV和H1N1神经系统作用的敏感性，从而导致与神经胶质细胞炎症激活相关的黑质中多巴胺能神经元的逐渐丧失。该假设将通过新的特定目的测试，该目标将评估MN的能力加剧WEEV/SINDBIS（TJALKENS）或H1N1（SMEYNE）感染的神经系统作用，并使用下一代序列/RNA-RNA-Seq（Slayden）评估了宿主性病原转录组反应。这是，我们的财团对i）进行协同，跨学科研究的Victer程序目标有很高的反应，ii）支持从潜水员学科和iii中的个体之间的知识交流和III）开发新的方法，以理解环境化学物质在疾病病因中的作用，从而影响临床或公共卫生实践。