Mechanisms of rotenone-induced neuroinflammation and Parkinsonism in aging mice

鱼藤酮诱导衰老小鼠神经炎症和帕金森病的机制

基本信息

批准号：
9115160
负责人：
Matthew Charles Havrda
金额：
$ 34.88万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9115160
关键词：
Address Aging Agricultural Workers Animal Model Anti-Inflammatory Agents Anti-inflammatory Astrocytes Biochemical Biological Models Blood Cells Brain Cells Chronic Data Detection Development Disease Disease Progression Dose Early Diagnosis Elderly Epidemiology Evaluation Studies Exposure to Farming environment Genetic Goals Gout Health Human Immune In Vitro Individual Infiltration Inflammation Mediators Inflammatory Interleukin-1 beta Intervention Leukocytes Mediating Metabolic Microglia Migration Assay Military Personnel Molecular Movement Mus Mutant Strains Mice National Institute of Environmental Health Sciences Neuraxis Neurodegenerative Disorders Occupational Exposure Parkinson Disease Parkinsonian Disorders Pathology Pathway interactions Pattern Peripheral Pesticides Pharmaceutical Preparations Phenotype Populations at Risk Post-Translational Protein Processing Preventive therapy Preventive treatment Property Proteins Proteomics Reporting Risk Risk Factors Role Rotenone Scientist Specificity Staging Stomach Symptoms Testing Tissues Toxic Environmental Substances Toxin age related alpha synuclein chemokine disabling symptom in vivo interest leukocyte activation mouse model nervous system disorder neuroinflammation novel research study small molecule synuclein translational study

项目摘要

DESCRIPTION (provided by applicant): The goal of this project is to characterize newly discovered cellular mechanisms of environmental toxin- induced neuroinflammation and determine if neuroinflammation is required and sufficient for the development of Parkinsonism in aging mice. In the large-scale Farming and Movement Evaluation Study (FAME), led by the National Institute of Environmental Health Sciences (NIEHS), exposure to the metabolic toxin rotenone has been identified as a risk factor in the development of Parkinson's disease (PD). With the goal of developing animal models recapitulating long-term occupational exposure to epidemiologically relevant environmental toxins, we exposed mice to low doses of rotenone using intra-gastric gavage, 5 days per week, continuously, for 5 months. Planned experiments build on our characterization of central nervous system (CNS) pathologies in rotenone treated mice during which we identified progressive neuroinflammatory changes occurring in association with the development of classical PD symptomology. Ongoing studies implicate the Nlrp3 inflammasome, an intracellular mediator of inflammation, in rotenone-induced neuroinflammation and suggest that prodromal anti-inflammatory treatment can block the progression of PD symptoms in rotenone treated mice. Our proposed aims will test key predictions made by our ongoing studies to determine the cellular origins of the rotenone-induced pro-inflammatory chemokine Cxcl1. In a second aim, we will use in vivo genetic and pharmacologic approaches to test the prediction that the Nlrp3-dependent neuroinflammation is required for the development of Parkinsonism in mice ingesting rotenone. In so doing, we will evaluate the specificity and efficacy of an investigational anti-inflammasome drug, BAY 11-7082, to determine if prodromal anti-Nlrp3 intervention can block the progression of Parkinsonism in aging rotenone-treated mice. Simultaneously, we will comprehensively characterize post-translational modification and aggregation of a-synuclein protein in the context of chronic rotenone exposure using a longitudinal approach. Using advanced biochemical and proteomic approaches, these studies will test the prediction that Nlrp3-mediated neuroinflammation can initiate a-synuclein aggregation and thereby cause Parkinsonism in aging mice. The completion of these studies is expected to have broad reaching implications for our understanding of neuroinflammation occurring as the result of long-term exposure to environmental toxins. Findings will inform the development of preventative treatments for neurologic disorders in at risk populations such as the elderly, agricultural workers and military personnel.

描述（由应用程序提供）：该项目的目的是表征新发现的环境毒素诱导的神经炎症的细胞机制，并确定是否需要神经炎症，并且足以发展衰老小鼠的帕金森氏症。在美国国家环境健康科学研究所（NIEHS）领导的大型农业和运动评估研究（名望）中，已经将暴露于代谢毒素烤烤甲烯酮的暴露被确定为帕金森氏病（PD）发展的危险因素。为了开发动物模型，概括了长期职业在流行病学上相关的环境毒素中，我们使用糖内饲料将小鼠暴露于低剂量的烤面包酮，每周连续5天，持续5个月。计划中的实验建立在我们对葡萄干治疗的小鼠中中枢神经系统（CNS）病理学的表征，在此期间我们确定了随着经典PD症状的发展而发生的进行性神经炎症变化。正在进行的研究暗示NLRP3炎症体是烤罗替酮诱导的神经炎症性的细胞内介体，这表明前后抗炎治疗可以阻止紫藤酮治疗的小鼠中PD症状的进展。我们提出的目标将测试我们正在进行的研究确定紫红酮诱导的促炎性趋化因子CXCL1的细胞起源的关键预测。在第二个目标中，我们将使用体内遗传和药物方法来测试预测NLRP3依赖性的神经炎症是摄入屋顶酮的小鼠中帕金森氏症发展所必需的。通过这样做，我们将评估研究性抗炎药的特异性和效率，即11-7082，以确定前驱抗NLRP3干预是否可以阻止prockinsism parkinsism在衰老的转子龙治疗小鼠中的进展。同时，我们将全面表征使用纵向方法在慢性屋顶酮暴露的背景下，A-突触核蛋白蛋白的翻译后修饰和聚集。使用先进的生化和蛋白质组学方法，这些研究将测试NLRP3介导的神经炎症可以启动A-核蛋白聚集的预测，从而导致衰老小鼠的帕金森氏症。这些研究的完成预计将对我们对长期暴露于环境毒素的导致神经炎症的理解具有广泛的影响。调查结果将为危险人群中的神经系统疾病的预防性治疗提供信息，例如老年人，农业工作者和军事人员。