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

项目摘要 帕金森病（PD）是一种影响中枢神经系统（CNS）的衰弱性运动障碍 并且是仅次于阿尔茨海默病（AD）的世界范围内第二常见的神经变性疾病。在 除了年龄和遗传背景外，环境暴露与 发展PD。与PD风险因素有关的药物包括杀虫剂和重金属， 如细菌和病毒等传染媒介。累积的环境暴露 在整个生命周期中使用这些药物可以促进PD和相关疾病的发展， 基本上没有答案。脑内胶质细胞的炎症激活被认为是一个关键的早期事件 在帕金森病的前驱期尽管如此，调节这种破坏性转化的分子信号 炎症表型现在才被阐明。此R35/RIVER应用解决了 问题是神经免疫轴如何对在整个环境中遇到的环境暴露作出反应。 寿命以及这些暴露的组合如何通过以下方式引发神经系统疾病的发作： 神经胶质细胞表型转化为神经毒性状态。为了更深入地了解 神经胶质细胞表型变化的分子调控，其是从前驱期进展到 症状性疾病，拟议的研究将采用先进的转基因模型和分子工具 来解决这些科学问题。这项申请中提出的关键科学问题围绕着 三个明确定义和相互关联的目标：1）确定发展如何暴露于环境 神经毒素调节神经胶质细胞中的先天性免疫信号传导，以改变神经胶质细胞的炎症反应。 神经免疫轴在老化过程中随后的毒性暴露，2）确定神经胶质细胞中的关键分子通路， 通过暴露于环境神经毒物而改变的细胞，调节大脑的炎症反应 病毒感染，以及3）阐明相应的神经胶质细胞区域群体中的分子特征 在神经系统疾病的进展过程中， 环境神经毒物和病毒。R35/RIVER应用程序所解决的科学目标 关于寿命期内的多次暴露和神经系统疾病的风险， 涉及暴露于多种神经毒性和感染性因子的研究，以及强有力的方法 例如高内容成像、基于神经网络的信息分析、单细胞和空间 转录组学和产生新的转基因模型。R35机制非常适合集成这些 复杂的资源和方法，以及解决基本问题所需的人员专业知识 关于环境暴露如何改变大脑的先天免疫反应， 神经系统疾病如PD和AD的发展。

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.