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 帕金森氏病(PD)是一种影响中枢神经系统(CNS)的衰弱运动障碍 是仅次于阿尔茨海默病(AD)的全球第二常见的神经退行性疾病。在……里面 除了年龄和遗传背景外，环境暴露与 帕金森病的发展。被认为是帕金森病危险因素的药物还包括杀虫剂和重金属。 作为细菌和病毒等感染性物质。累积的环境暴露如何 使这些药物终生可促进帕金森病的发展和相关疾病的残留 基本上无人接听。大脑中胶质细胞的炎性激活被认为是一种关键的早期事件 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 炎症表型直到现在才被阐明。此R35/River应用解决了关键的 神经免疫轴如何对环境暴露做出反应的问题 寿命，以及这些暴露的组合如何通过 神经胶质细胞的表型转化为神经毒性状态。更深入地了解 神经胶质细胞表型变化的分子调控 对于有症状的疾病，拟议的研究将使用复杂的转基因模型和分子工具 来解决这些科学问题。在这项申请中提出的关键科学问题围绕着 三个明确且相互关联的目标：1)决定发育如何暴露在环境中 神经毒素调节神经胶质细胞的先天免疫信号以改变炎症反应 衰老期间神经免疫轴与随后的毒性暴露，2)确定神经胶质细胞的关键分子通路 因暴露于调节脑部炎症反应的环境神经毒物而改变的细胞 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 在暴露于空气中引发的神经系统疾病进展过程中的各种激活状态 环境神经毒物和病毒。R35/River应用程序解决的科学目标 对于生命周期内的多次暴露和神经疾病的风险，将使用长期 涉及接触多种神经毒性和感染性物质的研究，以及强有力的方法 如高含量成像、基于神经网络信息分析、单细胞和空间 转录学和新转基因模型的产生。R35机制是集成这些功能的理想选择 具有解决基本问题所需的人员专业知识的复杂资源和方法 关于环境暴露如何改变大脑的先天免疫反应，从而促进 帕金森病和阿尔茨海默病等神经系统疾病的发展。

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.