Mechanisms of rotenone-induced neuroinflammation and Parkinsonism in aging mice

 描述(申请人提供)：这个项目的目标是描述新发现的环境毒素诱导的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氏症发展所必需的和充分的。在由美国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，接触代谢毒素鱼藤酮已被确定为帕金森氏病(PD)发生的风险因素。为了建立长期职业暴露于流行病学相关环境毒素的动物模型，我们通过小鼠灌胃给予小鼠低剂量鱼藤酮，每周5天，连续5个月。计划中的实验建立在我们对鱼藤酮治疗的小鼠中枢神经系统(CNS)病理特征的描述基础上，在此期间，我们确定了与经典PD症状的发展相关的进行性神经炎性变化。正在进行的研究表明，Nlrp3炎症小体，一种炎症的细胞内介质，与鱼藤酮诱导的神经炎症有关，并表明前驱抗炎治疗可以阻止鱼藤酮治疗小鼠帕金森病症状的进展。我们提出的目标将测试我们正在进行的研究中做出的关键预测，以确定鱼藤酮诱导的促炎趋化因子CXCL1的细胞来源。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Nlrp3依赖的神经炎症是摄入鱼藤酮的小鼠发生帕金森综合症所必需的预测。为此，我们将评估一种研究中的抗炎药Bay 11-7082的特异性和有效性，以确定前驱体抗Nlrp3干预是否可以阻止鱼藤酮治疗的老化小鼠帕金森病的进展。同时，我们将使用纵向方法综合表征在慢性鱼藤酮暴露的背景下a-突触核蛋白的翻译后修饰和聚集。利用先进的生物化学和蛋白质组学方法，这些研究将检验Nlrp3介导的神经炎症可以引发α-突触核蛋白聚集，从而导致老年小鼠帕金森症的预测。这些研究的完成有望对我们理解长期暴露于环境毒素所导致的神经炎症有广泛的影响。这些发现将为老年、农业工人和军事人员等高危人群神经疾病预防性治疗的发展提供信息。

 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.