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.

项目摘要 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。 我们在农药暴露小鼠和PD患者中的研究表明，与环境相关的细胞应激 毒物暴露激活细胞内炎性小体。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物。炎症小体 已经成为神经退行性疾病中炎症的关键介质，部分原因是它们可以感知 非微生物“无菌”炎症触发剂通常在慢性、年龄相关性疾病如PD中观察到。 在PD模型中鉴定的炎性体触发物包括杀虫剂、重金属、线粒体和氧化应激。 压力和蛋白质损伤，如错误折叠的突触核蛋白。我们最初的目标是， 与PD相关的杀虫剂鱼藤酮激活了NLRP 3-炎性体， 防止鱼藤酮诱导的黑质细胞损失。在平行的研究中，我们发现NLRP 3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 研究结果和在临床上针对NLRP 3的快速推进的努力为继续研究NLRP 3提供了令人信服的背景。 NLRP 3-炎性体在中枢神经系统中的活性分析。我们建议延长我们的 基于我们对NLRP 3-炎性小体活性的小胶质细胞和神经元起源的发现， 血浆炎性小体相关蛋白可能是一类新的毒物生物标志物 暴露和PD。我们已经开发了基于CRE-driven多巴胺神经元的创新小鼠模型， 小胶质细胞特异性Nlrp 3获得功能。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NLRP 3炎性体活性对神经炎症和黑质的贡献 神经变性在第二个目标中，我们将致力于了解我们的细胞机制。 检测PD患者血浆中的血浆传播炎性小体相关蛋白。这些研究将验证LC- MS/MS研究中，我们确定了Nlrp 3依赖性的胞吐介质布鲁顿激酶释放 (BTK)Coronin1A（Coronin1A）我们提出了系统的NLRP 3，BTK和CORO 1A功能的获得和丧失 在暴露于转基因农药的小胶质细胞、神经元和单核细胞系中进行的研究， 新的分泌机制，并定义脑细胞类型特异性NLRP 3依赖性分泌组。研究将 提供机制数据并定义由痛苦脑细胞特异性分泌的分子， 为开发诊断工具以检测、分层和监测PD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来应对与年龄相关的神经退行性疾病迅速增加的全球负担： 表征多种疾病的共同途径，这些疾病可以通过已经存在或正在出现的 小分子疗法