Mechanisms and indicators of inflammasome signaling in Parkinson’s disease

帕金森病炎症小体信号传导机制和指标

• 批准号: 10310571
• 负责人: Matthew Charles Havrda
• 金额: $ 67.32万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10310571
• 关键词: Address; Anti-Inflammatory Agents; Attenuated; Biological Assay; Biology; Blood specimen; Bone Marrow; Cell Death; Cells; Cellular Stress; Chronic; Clinical Data; Clinical Trials; Complex; Data; Data Set; Development; Diagnostic; Disease model; Employment; Exposure to; Foundations; GTP-Binding Protein Regulators; GTP-Binding Proteins; Heavy Metals; Homeostasis; Immune; Immune response; Immune system; Immunology; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Innate Immune System; Intervention; Mediating; Medical center; Military Personnel; Mitochondria; Modeling; Molecular; Monitor; Mus; Myelogenous; Myeloid Cells; Nerve Degeneration; Neurodegenerative Disorders; Occupations; Oxidative Stress; Parkinson Disease; Participant; Pathogenesis; Patients; Pattern Recognition; Peripheral; Pesticides; Pharmaceutical Preparations; Phenotype; Pilot Projects; Plasma; Populations at Risk; Process; Proteins; RGS Proteins; Reporting; Research; Resolution; Risk; Rivers; Role; Rotenone; Signal Transduction; Signaling Protein; Site; Surveys; Symptoms; System; Time; Toxic Environmental Substances; Toxicant exposure; Work; age related neurodegeneration; associated symptom; base; cell injury; cell type; clinically relevant; cytokine; epidemiologic data; experience; follow-up; gain of function; gene environment interaction; improved; innovation; lifestyle data; macrophage; military veteran; motor impairment; mouse model; neuroinflammation; neuropathology; patient population; pesticide exposure; pre-clinical; response; symptomatology; tool; toxicant

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.

项目概要 ViCTER 联盟的成立是为了表征外周炎症机制 骨髓免疫区室，确定它们对农药驱动的神经变性的影响，并看看血浆是否 这些过程的指标与军事占领和帕金森病（PD）有关。这是 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。我们在农药方面的工作- 暴露的小鼠和 PD 患者表明环境毒物聚集在 NLRP3 炎性体上。 炎症小体是细胞内多蛋白模式识别复合物，可启动和传播 炎症反应与细胞焦亡细胞可逆过程相关的细胞损伤和应激 死亡。 NLRP3 炎症小体已成为 PD 炎症的关键介质，部分原因是它可以 感知通常与慢性、年龄相关的神经退行性疾病相关的非微生物炎症触发因素 失调。 PD 模型中发现的 NLRP3 炎症小体触发因素包括农药、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全身性的 人们越来越认识到外周免疫系统在对毒物和毒素的反应中的作用。 PD 的进展。表征外周免疫细胞中与 PD 相关的机制可能有助于识别 与 PD 进展相关的特征。我们对全身暴露于鱼藤酮的小鼠进行的研究确定了 Nlrp3 依赖性外周免疫反应与黑质神经变性同时发生。我们对PD的研究 患者发现了易于检测的血浆中 NLRP3 炎性体活性指标并升高 PD患者血浆NLRP3蛋白，可能与军事就业有关。这些数据提供了 我们提出的 PD 背景下外周 NLRP3 活性表征的令人信服的背景。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 限制 Nlrp3 表达到外周骨髓细胞并表征外周免疫反应， 使用已建立的基于鱼藤酮暴露的 PD 模型来研究神经炎症和黑质神经变性。在 第二个目标是，我们跟进试点研究，以确定抗炎神经保护蛋白是否 G 蛋白信号传导调节器 10 (RGS10) 的作用是解析 NLRP3 炎症小体信号传导。在第三个 我们的目标是与 White River Junction VA 医疗中心合作，评估具有军事经验的受试者， 使用已建立的测定法来表征循环炎症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 NLRP3 和基于毒物的专家 PD、RGS10 和 PD 相关免疫学模型以及基于患者的研究。合作者将聘用 跨学科策略来表征临床相关炎症机制和炎症小体 高危患者群体中的活动。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疗法。