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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.