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。

基本信息

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
项目类别：
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

项目摘要

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氏病（PD）的事件和进展的基础。我们在暴露于农药的小鼠和PD患者中的工作表明，与环境相关的细胞应激毒物暴露会激活细胞内炎症。炎症是细胞内多蛋白含有启动和传播注射的模式识别受体的复合物。炎症已经成为神经退行性疾病中炎症的关键介体，部分原因是它们可以感觉到在慢性，年龄相关的疾病（如PD）中，通常观察到的非微生物“无菌”炎症触发因素。在PD模型中鉴定出的炎性体触发器包括农药，重金属，线粒体和氧化压力和蛋白质侮辱，例如突触核蛋白错误折叠。我们最初的目标确定了长期曝光到与PD相关的农药rotorone激活了NLRP3-炎症体，而Nlrp3 - / - 小鼠是免受紫藤酮诱导的果膜损失的保护。在平行研究中，我们确定了NLRP3表达的升高与健康的志愿者相比，PD患者的脑脑组织和血浆退化。这些发现和迅速促进临床中NLRP3的努力为持续提供了令人信服的背景分析中枢神经系统中NLRP3-炎症体的活性。我们建议扩展我们的基于我们对NLRP3-炎症体活动的小胶质细胞和神经元起源的发现和血浆传播炎症相关蛋白的概念可能是有毒物质的新型生物标志物暴露和PD。我们已经开发了基于CRE驱动的多巴胺神经元的创新鼠标模型，并且小胶质特异性NLRP3功能。我们将利用我们已建立的鱼藤酮暴露模型来剖析细胞型特异性NLRP3炎性体活动对神经炎症和nigral的贡献神经变性。在第二个目标中，我们将努力了解我们的细胞机制 PD患者血浆中血浆传播炎症体相关蛋白的检测。这些研究将验证LC- MS/MS研究，我们确定了胞外增生介质的NLRP3依赖性释放Bruton激酶（BTK）和Coronin1a（Coro1a）。我们提出了系统的NLRP3，BTK和Coro1a的功能增益和损害在一般修饰的农药暴露的小胶质细胞，神经元和单核细胞系中的研究以表征新颖的分泌机制并定义了脑细胞型特异性NLRP3依赖性分泌组。研究将提供机械数据并定义由遇难的脑细胞专门分泌的分子，提供开发诊断工具以检测，分层和监视PD的基础。我们的研究很重要因为我们通过通过表征可以针对已经存在或已出现的多种疾病共同的途径小分子疗法。