Deciphering innate immune signaling mechanisms in glial cells linking lifetime environmental exposures to neuroinflammation, protein aggregation and neurodegeneration in Parkinsons disease

破译神经胶质细胞中的先天免疫信号机制，将终生环境暴露与帕金森病的神经炎症、蛋白质聚集和神经变性联系起来

• 批准号: 10642309
• 负责人: RONALD TJALKENS
• 金额: $ 113.94万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-12 至 2031-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10642309
• 关键词: Address; Affect; Age; Aging; Alzheimer' s Disease; Bacteria; Brain; Cells; Central Nervous System; Complex; Development; Disease; Environmental Exposure; Event; Exposure to; Generations; Genetic; Goals; Heavy Metals; Human Resources; Image; Immune signaling; Infectious Agent; Inflammatory; Inflammatory Response; Informatics; Innate Immune Response; Link; Longevity; Longitudinal Studies; Molecular; Molecular Profiling; Movement Disorders; Nerve Degeneration; Network-based; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neuroglia; Neuroimmune; Neurotoxins; Parkinson Disease; Pathway interactions; Pesticides; Phase; Phenotype; Population; Regulation; Resources; Risk; Risk Factors; Signal Transduction; Toxic Environmental Substances; Toxicant exposure; Transgenic Model; Virus; Virus Diseases; glial activation; nervous system disorder; neural network; neuroinflammation; neurotoxic; pathogen; protein aggregation; tool; transcriptomics

Project Summary Parkinson’s disease (PD) is a debilitating movement disorder affecting the central nervous system (CNS) and is the second most common neurodegenerative disease worldwide after Alzheimer’s disease (AD). In addition to age and genetic background, environmental exposures are strongly associated with the development of PD. Agents implicated as risk factors for PD include pesticides and heavy metals, as well as infectious agents such as bacteria and viruses. The question of how cumulative environmental exposure to these agents throughout lifespan can promote the development of PD and related disorders remains largely unanswered. Inflammatory activation of glial cells in the brain is recognized as a critical early event in the prodromal phase of PD. Still, the molecular signals regulating conversion to this damaging inflammatory phenotype are only now being elucidated. This R35/RIVER application addresses the critical question of how the neuro-immune axis responds to environmental exposures encountered across the lifespan and how the combination of such exposures can trigger the onset of neurological disease through phenotypic conversion of glial cells to a neurotoxic state. To develop a deeper understanding of the molecular regulation of phenotypic changes in glial cells that underlie the progression from prodromal to symptomatic disease, the proposed studies will employ sophisticated transgenic models and molecular tools to address these scientific questions. The key scientific questions raised in this application coalesce around three well defined and interrelated goals: 1) Determine how developmental exposure to environmental neurotoxins modulates innate immune signaling in glial cells to alter the inflammatory response of the neuro-immune axis to subsequent toxic exposures during aging, 2) Identify key molecular pathways in glial cells altered by exposure to environmental neurotoxicants that regulate inflammatory responses of the brain to viral infection, and 3) Elucidate molecular signatures in regional populations of glial cells corresponding to various states of activation across the progression of neurological disease triggered by exposure to environmental neurotoxicants and viruses. The scientific goals addressed by this R35/RIVER application concerning multiple exposures across lifespan and risk for neurological disease will use both long-term studies involving exposure to multiple neurotoxic and infectious agents, as well as powerful approaches such as high-content imaging, neural network-based informatic analysis, single-cell and spatial transcriptomics and generation of new transgenic models. The R35 mechanism is ideal for integrating these complex resources and approaches with the personnel expertise necessary to address fundamental questions about how environmental exposures alter innate immune responses of the brain that promote the development of neurological disorders like PD and AD.

项目摘要 帕金森氏病（PD）是一种影响中枢神经系统（CNS）的令人衰弱的运动障碍 这是仅次于阿尔茨海默氏病（AD）的全球第二常见神经退行性疾病。在 除了年龄和遗传背景，环境暴露与 PD的开发。作为PD危险因素实施的代理也包括农药和重金属， 作为细菌和病毒等传染剂。累积环境暴露的问题 在整个生命周期中，这些代理可以促进PD的发展，相关疾病仍然存在 在很大程度上没有得到答复。大脑中神经胶质细胞的炎症激活被认为是关键的早期事件 在PD的前驱阶段。尽管如此，调节转换为这种破坏的分子信号仍然 炎症表型现在才阐明。此R35/河流应用程序解决了关键 关于神经免疫轴对环境暴露的反应如何在整个环境中遇到的问题 寿命以及这种暴露的结合如何通过 神经胶质细胞向神经毒性状态的表型转化。为了深入了解 神经胶质细胞中表型变化的分子调节，这些变化是从前代到前进的发展的基础 有症状的疾病，拟议的研究将采用复杂的转基因模型和分子工具 解决这些科学问题。本应用程序中提出的关键科学问题围绕 三个定义良好和相互关联的目标：1）确定发展环境的发展如何 神经毒素调节神经胶质细胞中的先天免疫信号传导，以改变 在衰老期间，神经免疫轴直至随后的毒性暴露，2）识别胶质的关键分子途径 通过暴露于调节大脑炎症反应的环境神经毒性而改变的细胞 引起病毒感染，3）阐明胶质细胞区域种群中的分子特征 在各种暴露于神经系统疾病进展中的激活状态 环境神经毒性和病毒。此R35/River应用程序所针对的科学目标 涉及寿命的多次暴露和神经疾病的风险将使用长期使用 涉及暴露于多种神经毒性和感染剂的研究以及强大的方法 例如高含量成像，基于神经网络的信息分析，单细胞和空间 新转基因模型的转录组学和生成。 R35机制是整合这些机制 与解决基本问题所需的人员专业知识相关的复杂资源和方法 关于环境暴露如何改变促进大脑的先天免疫反应 PD和AD等神经系统疾病的发展。