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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要已经建立了Victer联盟以表征周围炎症机制髓样免疫室，确定它们对农药驱动神经变性的影响，并查看血浆是否存在这些过程的传播指标与军事占领和帕金森氏病（PD）有关。这是广泛接受了复杂的基因环境相互作用是PD风险。我们在农药中的工作 - 暴露的小鼠和PD患者表明，环境有毒物质会在NLRP3炎性体上融合。炎症是启动和传播的细胞内多蛋白质模式识别复合物响应于细胞损伤和与凋亡细胞可逆过程相关的压力的炎症死亡。 NLRP3炎性体已成为PD炎症的关键介体，部分原因是它可以有义务非微生物炎症性触发因素，通常与慢性，年龄相关的神经退行性相关疾病。在PD模型中鉴定出的NLRP3炎性触发器包括农药，重金属，线粒体和氧化应激以及蛋白质损伤。环境有毒物质的暴露通常是全身性的而且，对外围免疫系统在对毒物的反应中的作用越来越欣赏 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鉴定与PD进展相关的签名。我们在全身暴露于鱼藤酮的小鼠中的研究鉴定了 NLRP3依赖性的外周免疫响应与ni骨神经变性同时发生。我们对PD的研究患者确定了NLRP3炎性体活动的易于检测到的血浆传播指标 PD患者的血浆NLRP3蛋白，可能与军事就业有关。这些数据提供了在PD背景下，我们提出的外围NLRP3活性的表征引人入胜的背景。我们已经开发了基于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表达限制为周围髓样细胞，并表征外周免疫反应，使用已建立的基于屋顶的PD模型的神经炎症和神经变性。在第二个目的，我们跟进初步研究，以确定抗炎神经保护蛋白是否是否 G蛋白信号传导10（RGS10）函数的调节剂可以解决NLRP3-炎症体信号传导。三分之一 AIM，我们与White River Junction VA医疗中心合作，评估具有先前军事经验的对象，使用已建立的acas来表征循环炎性蛋白之间的关系，军事占领和PD。我们的Victer财团汇集了NLRP3的专家和基于毒物的专家 PD，RGS10和PD相关免疫学的模型以及基于患者的研究。合作者将采用跨学科的策略来表征临床相关的炎症机制和炎症体在高危患者人群中的活动。研究将为开发诊断工具的开发提供基础和监测，分层和治疗PD的疗法。