Mechanisms of pesticide-induced neuroinflammation and parkinsonism in aging mice.

农药引起衰老小鼠神经炎症和帕金森病的机制。

• 批准号: 10569052
• 负责人: Matthew Charles Havrda
• 金额: $ 40.66万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-09 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10569052
• 关键词: Aging; Agricultural Workers; Alleles; Animals; Autopsy; Behavior; Biological; Biological Markers; Biology; Blood; Brain; Cell Death; Cell Line; Cells; Cellular Stress; Central Nervous System; Chronic; Clinic; Clinical Trials; Complex; Data; Detection; Development; Disease; Disinhibition; Distress; Drug Targeting; Etiology; Exocytosis; Exposure to; Foundations; Genetic; Heavy Metals; Hyperactivity; Incidence; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Mediating; Mediator; Microglia; Mitochondria; Modeling; Monitor; Multiprotein Complexes; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Organism; Oxidative Stress; Parkinson Disease; Parkinsonian Disorders; Pathway interactions; Patients; Pattern recognition receptor; Pesticides; Pharmaceutical Preparations; Phosphotransferases; Plasma; Predisposition; Process; Proteins; Publishing; Reporting; Risk; Role; Rotenone; Signal Transduction; Sterility; Symptoms; Testing; Therapeutic Agents; Time; Tissues; Toxic Environmental Substances; Toxicant exposure; Translating; Validation; Vesicle; Whole Organism; Work; age related; age related neurodegeneration; brain cell; candidate identification; cell type; cohort; combat; cytokine; design; diagnostic tool; dopaminergic neuron; gain of function; gene environment interaction; healthy volunteer; improved; innovation; liquid chromatography mass spectrometry; loss of function; monocyte; mouse model; neuroinflammation; neuroprotection; novel; paracrine; pesticide exposure; promoter; small molecule therapeutics; symptomatology; synuclein; toxicant; translational study

PROJECT SUMMARY Complex gene-environment interactions underlie the incidence and progression of Parkinson’s disease (PD). Our work in pesticide-exposed mice and PD patients indicates that cellular stress associated with environmental toxicant exposure activates the intracellular inflammasomes. Inflammasomes are intracellular multi-protein complexes containing pattern recognition receptors that initiate and propagate inflammation. Inflammasomes have emerged as key mediators of inflammation in neurodegenerative diseases in part because they can sense non-microbial “sterile” inflammatory triggers commonly observed in chronic, age-related disorders like PD. Inflammasome triggers identified in models of PD include pesticides, heavy metals, mitochondrial and oxidative stress, and proteinaceous insults like misfolded synuclein. Our original aims determined that long-term exposure to the PD-associated pesticide rotenone activated the NLRP3-inflammasome and that Nlrp3-/- mice were protected from rotenone-induced nigral cell loss. In parallel studies, we identified elevated NLRP3 expression in degenerating mesencephalic tissues and plasma in PD patients compared with healthy volunteers. These findings and rapidly advancing efforts to target NLRP3 in the clinic provide a compelling backdrop for continued analysis of the activities of the NLRP3-inflammasome in the central nervous system. We propose to extend our studies based on our findings of both microglial and neuronal origins for NLRP3-inflammasome activity and the concept that plasma borne inflammasome-related proteins may be a novel class of biomarkers for toxicant exposure and PD. We’ve developed innovative mouse models based on CRE-driven dopamine neuron and microglial specific Nlrp3 gain-of function. We will utilize our established rotenone exposure model to dissect the contributions of cell-type specific NLRP3 inflammasome activity to neuroinflammation and nigral neurodegeneration. In a second aim, we will work to understand the cellular mechanisms that underlie our detection of plasma-borne inflammasome related proteins in PD patient plasma. These studies will validate LC- MS/MS studies in which we identified Nlrp3-dependent release of the exocytosis mediators Bruton’s Kinase (BTK) and Coronin1A (CORO1A). We propose systematic NLRP3, BTK, and CORO1A gain-and-loss of function studies in genetically modified pesticide-exposed microglial, neuronal, and monocytic cell lines to characterize novel secretory mechanisms and define brain-cell-type specific NLRP3-dependent secretomes. Studies will provide mechanistic data and define molecules secreted specifically by distressed brain cells providing a foundation for the development of diagnostic tools to detect, stratify, and monitor PD. Our study is important because we work to combat the rapidly increasing global burden of age-related neurodegenerative disorders by characterizing a pathway common to multiple diseases that can be targeted with already existing or emerging small molecule therapeutics.

项目概要 复杂的基因-环境相互作用是帕金森病 (PD) 发病和进展的基础。 我们对接触农药的小鼠和帕金森病患者的研究表明，细胞应激与环境有关 有毒物质暴露会激活细胞内炎症小体。炎症小体是细胞内的多蛋白 含有引发和传播炎症的模式识别受体的复合物。炎症小体 已成为神经退行性疾病炎症的关键介质，部分原因是它们可以感知 非微生物“无菌”炎症触发因素通常在帕金森病等慢性、与年龄相关的疾病中观察到。 PD 模型中发现的炎症小体触发因素包括农药、重金属、线粒体和氧化 压力和蛋白质损伤，例如错误折叠的突触核蛋白。我们最初的目标决定了长期暴露 PD 相关农药鱼藤酮激活了 NLRP3 炎症小体，并且 Nlrp3-/- 小鼠 防止鱼藤酮诱导的黑质细胞损失。在平行研究中，我们发现 NLRP3 表达升高 与健康志愿者相比，PD患者的中脑组织和血浆退化。这些 研究结果和临床上针对 NLRP3 的快速推进努力为持续的研究提供了令人信服的背景 分析中枢神经系统中 NLRP3 炎症小体的活性。我们建议延长我们的 基于我们对 NLRP3 炎症小体活性的小胶质细胞和神经元起源的发现以及 血浆炎性体相关蛋白可能是一类新型毒物生物标志物的概念 曝光和 PD。我们开发了基于 CRE 驱动的多巴胺神经元的创新小鼠模型 小胶质细胞特异性 Nlrp3 增益功能。我们将利用我们建立的鱼藤酮暴露模型来剖析 细胞类型特异性 NLRP3 炎症小体活性对神经炎症和黑质的贡献 神经变性。第二个目标是，我们将努力了解构成我们生命基础的细胞机制。 检测 PD 患者血浆中血浆传播的炎性体相关蛋白。这些研究将验证 LC- 我们在 MS/MS 研究中发现了胞吐作用介质 Bruton 激酶的 Nlrp3 依赖性释放 (BTK) 和 Coronin1A (CORO1A)。我们提出了系统的 NLRP3、BTK 和 CORO1A 函数得失 对暴露于转基因农药的小胶质细胞、神经元和单核细胞系进行研究，以表征 新的分泌机制并定义了脑细胞类型特异性 NLRP3 依赖性分泌组。研究将 提供机械数据并定义由不良脑细胞专门分泌的分子，提供 为开发检测、分层和监测 PD 的诊断工具奠定了基础。我们的学习很重要 因为我们致力于通过以下方式对抗迅速增加的与年龄相关的神经退行性疾病的全球负担 描述多种疾病共有的途径，可以针对现有或新出现的疾病 小分子疗法。