Mechanisms and indicators of inflammasome signaling in Parkinson’s disease

项目总结 已建立Victer联合体来表征外周炎症的机制 髓系免疫隔膜，确定它们对杀虫剂驱动的神经退行性变的影响，并看看血浆- 这些过程的固有指标与军事占领和帕金森氏病(PD)有关。它是 人们普遍认为，复杂的基因-环境相互作用是帕金森病风险的基础。我们在杀虫剂方面的工作- 暴露的小鼠和帕金森病患者表明，环境毒物聚集在NLRP3炎症体上。 炎性小体是细胞内启动和传播的多蛋白质模式识别复合体 炎症反应与细胞损伤和应激相关的可逆过程中的焦虑性细胞 死亡。NLRP3炎症小体已成为帕金森病炎症反应的关键介质，部分原因是它可以 感觉性非微生物炎症触发因素通常与慢性、年龄相关的神经退行性变有关 精神错乱。在帕金森病模型中发现的NLRP3炎症小体触发因素包括杀虫剂、重金属、 线粒体和氧化应激，以及蛋白质损伤。环境毒物暴露通常是系统性的 越来越多的人认识到外周免疫系统在对毒物和 帕金森病的进展。表征外周免疫细胞中与帕金森病相关的机制可能有助于识别 与帕金森病进展相关的签名。我们在系统暴露于鱼藤酮的小鼠身上的研究发现 依赖NLRP3的外周免疫反应与黑质神经变性共存。我们对帕金森病的研究 患者发现容易检测到的NLRP3炎性小体活动和升高的血浆指标 帕金森病患者血浆NLRP3蛋白，可能与军队服役有关。这些数据提供了一个 为我们提出的PD背景下外周NLRP3活动的特征提供了令人信服的背景。我们 开发了基于CRE驱动的细胞型特异性Nlrp3功能增益的创新小鼠模型。我们会 将Nlrp3的表达限制在外周髓系细胞，并表征外周免疫反应， 使用已建立的基于鱼藤酮的帕金森病模型的神经炎症和黑质神经变性。在……里面 第二个目标是，我们对先导研究进行后续研究，以确定抗炎神经保护蛋白 G蛋白信号转导调节因子10(RGS10)的功能是解决NLRP3炎症体信号转导。在三分之一 目的，我们与白河交界处退伍军人医疗中心合作评估有军事经验的受试者， 使用已建立的检测方法来表征循环中的炎症体相关蛋白之间的关系， 军事占领和警察局。我们的Victer联盟汇集了NLRP3和基于毒物的专家 帕金森病、RGS10和帕金森病相关免疫学模型和以患者为基础的研究。合作者将采用 确定临床相关炎症机制和炎症体的跨学科策略 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、分层和治疗帕金森病的治疗方法。

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.