Mechanisms and indicators of inflammasome signaling in Parkinson’s disease

项目摘要 已建立ViCTER联盟，以表征外周炎症的机制。 骨髓免疫区室，确定它们对农药驱动的神经变性的影响，并看看血浆- 这些过程的指标与军事占领和帕金森病（PD）有关。是 人们普遍认为，复杂的基因-环境相互作用是PD风险的基础。我们在农药领域的工作- 暴露的小鼠和PD患者表明环境毒物聚集在NLRP 3炎性体上。 炎性小体是细胞内多蛋白模式识别复合物， 炎症反应与细胞损伤和应激有关的可逆过程中的pyroptotic细胞 死亡NLRP3炎性体已经成为PD中炎症的关键介质，部分原因是它可以 感觉非微生物炎症触发通常与慢性，年龄相关的神经退行性疾病 紊乱在PD模型中鉴定的NLRP3炎性体触发物包括杀虫剂、重金属， 线粒体和氧化应激以及蛋白质损伤。环境毒物暴露往往是全身性的 人们越来越认识到外周免疫系统在对毒物的反应中的作用， PD的进展。表征外周免疫细胞中PD相关机制可能有助于识别 与PD进展相关的签名。我们在全身暴露于鱼藤酮的小鼠中进行的研究发现， nlrp3依赖性外周免疫反应与黑质神经变性共同发生。我们对PD的研究 患者识别出容易检测到的NLRP 3炎性小体活性的血浆携带指标， PD患者血浆NLRP3蛋白，可能与军事就业有关。这些数据提供了一个 这是我们提出的在PD背景下表征外周NLRP 3活性的令人信服的背景。我们 开发了基于CRE驱动的细胞类型特异性Nlrp3功能获得的创新小鼠模型。我们将 将Nlrp3表达限制于外周骨髓细胞并表征外周免疫应答， 神经炎症和黑质神经变性使用建立的基于鱼藤酮的PD模型。在 第二个目标是，我们跟踪试点研究，以确定抗炎神经保护蛋白是否 G蛋白信号转导调节因子10（RGS10）的功能是解决NLRP 3-炎性体信号转导。在第三 目的是，我们与白河交汇处退伍军人医疗中心合作，评估有军事经验的受试者， 使用已建立的测定来表征循环炎性小体相关蛋白之间的关系， 军事占领和PD。我们的ViCTER联盟汇集了NLRP 3和基于毒物的 PD、RGS10和PD相关免疫学模型以及基于患者的研究。合作者将雇用 表征临床相关炎症机制和炎性小体的跨学科策略 在高危患者人群中的活动。研究将为诊断工具的开发提供基础 以及监测、分层和治疗PD的疗法。

PROJECT SUMMARY The ViCTER Consortium has been established to characterize mechanisms of inflammation in the peripheral myeloid immune compartment, determine their impact on pesticide-driven neurodegeneration, and see if plasma- borne indicators of these processes are associated with military occupation and Parkinson’s disease (PD). It is widely accepted that complex gene-environment interactions underlie the risk of PD. Our work in pesticide- exposed mice and PD patients indicates that environmental toxicants converge on the NLRP3 inflammasome. Inflammasomes are intracellular multi-protein pattern recognition complexes that initiate and propagate inflammation in response to cellular damage and stress associated with the reversible process of pyroptotic cell death. The NLRP3 inflammasome has emerged as a key mediator of inflammation in PD, in part because it can sense non-microbial inflammatory triggers commonly associated with chronic, age-related neurodegenerative disorders. NLRP3 inflammasome triggers identified in models of PD include pesticides, heavy metals, mitochondrial and oxidative stress, and proteinaceous insult. Environmental toxicant exposure is often systemic and there is a growing appreciation of the role of the peripheral immune system in the response to toxicants and the progression of PD. Characterizing PD-related mechanisms in peripheral immune cells may help to identify signatures relevant to the progression of PD. Our studies in mice systemically exposed to rotenone identify a Nlrp3-dependent peripheral immune response co-occurring with nigral neurodegeneration. Our study of PD patients identified easily detectable plasma-borne indicators of NLRP3 inflammasome activity and elevated plasma NLRP3 protein in PD patients, potentially related to military employment. These data provide a compelling backdrop for our proposed characterization of peripheral NLRP3 activity in the context of PD. We have developed innovative mouse models based on CRE-driven cell-type specific Nlrp3 gain-of-function. We will limit Nlrp3 expression to peripheral myeloid cells and characterize the peripheral immune response, neuroinflammation, and nigral neurodegeneration using an established rotenone exposure-based PD model. In a second aim, we follow up on pilot studies to determine if the anti-inflammatory neuroprotective protein Regulator of G-protein Signaling 10 (RGS10) functions to resolve NLRP3-inflammasome signaling. In a third Aim, we team with the White River Junction VA Medical Center to evaluate subjects with prior military experience, using established assays to characterize the relationship between circulating inflammasome-related proteins, military occupation, and PD. Our ViCTER Consortium brings together experts in NLRP3 and toxicant-based models of PD, RGS10 and PD-related immunology, and patient-based studies. The collaborators will employ interdisciplinary strategies to characterize clinically relevant inflammatory mechanisms and inflammasome activity in an at-risk patient population. Studies will provide a foundation for the development of diagnostic tools and therapies to monitor, stratify, and treat PD.