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

• 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
• 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

 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（由申请人提供）：本项目的目的是表征新发现的环境毒素诱导神经炎症的细胞机制，并确定神经炎症是否是老年小鼠帕金森症发展所必需的和充分的。在由国家环境健康科学研究所（NIEHS）领导的大规模农业和运动评估研究（FAME）中，暴露于代谢毒素鱼藤酮已被确定为帕金森病（PD）发展的风险因素。为了开发动物模型重现长期职业暴露于流行病学相关的环境毒素，我们将小鼠暴露于低剂量的鱼藤酮，每周灌胃5天，连续5个月。计划的实验建立在我们对鱼藤酮治疗小鼠中枢神经系统（CNS）病理学的表征基础上，在此期间，我们确定了与经典PD病理学发展相关的进行性神经炎症变化。正在进行的研究涉及Nlrp 3炎性体，一种细胞内炎症介质，在鱼藤酮诱导的神经炎症，并表明前驱抗炎治疗可以阻止在鱼藤酮治疗的小鼠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所做的关键预测，以确定鱼藤酮诱导的促炎趋化因子Cxcl 1的细胞起源。在第二个目标中，我们将使用体内遗传学和药理学方法来测试Nlrp 3依赖性神经炎症是小鼠摄入鱼藤酮后帕金森病发展所需的预测。在这样做时，我们将评估研究性抗炎体药物BAY 11-7082的特异性和功效，以确定前驱抗Nlrp 3干预是否可以阻断衰老鱼藤酮治疗小鼠中帕金森症的进展。同时，我们将全面表征翻译后修饰和聚合的α-突触核蛋白蛋白的背景下，慢性鱼藤酮暴露使用纵向的方法。使用先进的生物化学和蛋白质组学方法，这些研究将测试Nlrp 3介导的神经炎症可以引发α-突触核蛋白聚集并从而导致衰老小鼠帕金森症的预测。这些研究的完成预计将对我们理解长期暴露于环境毒素导致的神经炎症产生广泛的影响。研究结果将为老年人、农业工人和军人等高危人群的神经系统疾病预防性治疗的发展提供信息。