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.

项目总结 复杂的基因-环境相互作用是帕金森病(PD)发生和发展的基础。 我们在接触农药的小鼠和帕金森病患者中的研究表明，细胞应激与环境有关 接触毒物会激活细胞内的炎性小体。炎性小体是细胞内的多蛋白质 含有启动和传播炎症的模式识别受体的复合体。炎性小体 已经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觉到 非微生物的“无菌”炎症诱因通常见于帕金森病等慢性、与年龄相关的疾病。 在帕金森病模型中发现的炎性小体触发因素包括杀虫剂、重金属、线粒体和氧化 压力，以及蛋白质的侮辱，比如错误折叠的突触核蛋白。我们的初衷决定了长期接触 对Pd相关杀虫剂鱼藤酮激活NLRP3-炎症体和Nlrp3-/-小鼠 保护不受鱼藤酮诱导的黑质细胞丢失。在平行研究中，我们发现NLRP3在 帕金森病患者的中脑组织和血浆退行性变与健康志愿者的比较。这些 临床上针对NLRP3的发现和快速推进的努力为继续提供了令人信服的背景 中枢神经系统中NLRP3-炎症体的活性分析。我们建议延长我们的 基于我们关于NLRP3-炎症体活性的小胶质细胞和神经元来源的研究结果，以及 血浆炎症体相关蛋白可能是一类新的毒物生物标志物 暴露和警局。我们开发了基于CRE驱动的多巴胺神经元和 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 细胞型特异性NLRP3炎症体活性在神经炎症和黑质中的作用 神经退行性变。在第二个目标中，我们将致力于了解构成我们的 帕金森病患者血浆炎性小体相关蛋白的检测这些研究将验证LC- MS/MS研究中，我们确定了胞吐调节介质Bruton‘s Kinase依赖于Nlrp3的释放 (BTK)和Coronin1a(CORO1a)。我们提出了系统的NLRP3、BTK和CORO1A增损函数 转基因农药暴露的小胶质细胞、神经元和单核细胞系的研究 新的分泌机制和定义脑细胞类型的NLRP3依赖的分泌体。研究将会 提供机械数据并定义由受损脑细胞专门分泌的分子，提供 为开发诊断工具以检测、分层和监控PD奠定了基础。我们的研究很重要 因为我们致力于抗击全球迅速增加的与年龄相关的神经退行性疾病的负担，方法是 以多种疾病的共同途径为特征的，这些疾病可以针对已经存在或正在出现的疾病 小分子疗法。