Endotoxin Exposure and Risk of Parkinsonism

描述（由申请人提供）：本申请旨在建立一个由三个研究小组组成的转化/跨学科研究虚拟联盟（ViCTER），这些研究小组从事帕金森病（包括帕金森病（PD））的环境原因的流行病学、转化和基础科学研究。该联盟的努力将扩大正在进行的上海纺织女工暴露于内毒素（脂多糖[LPS]）中PS的流行病学研究。脂多糖是一种广泛存在的环境炎症原，是黑质纹状体细胞损伤和死亡的有效诱导剂。事实上，一个令人信服的lps诱导的啮齿动物实验模型概括了人类的病理特征和运动效应。通过促炎介质间接激活小胶质细胞的神经炎症被认为是脂多糖诱导的PS的主要发病机制。革兰氏阴性菌是脂多糖的来源，研究队列中的大量脂多糖暴露来自棉花处理和加工。研究人员之前已经量化了正在进行的PS和癌症研究的队列成员中的LPS暴露。由Checkoway博士指导的母项目（R01E5017462）的目的是评估量化职业LPS暴露与临床验证的PS风险、严重程度和进展之间的剂量-反应关系。该项目的新组成部分将纳入外周蛋白和遗传生物标志物，这些标志物可能作为风险指标，进一步表征LPS机制途径，并确定与LPS-PS途径相关的遗传易感性因素。本应用程序的目的是：1)表征与神经炎症和氧化/亚氧化（氧化还原）应激相关的血浆和唾液生物标志物，包括细胞因子/趋化因子、补体3 （C3）、因子H （FH）、1-突触核蛋白、DJ-1 （PARK7）、蛋白二硫异构酶（PDI）、PTEN诱导的推定激酶1 （PINK1）、泛素羧基末端酯酶L1 （UCHL1）和帕金（PARK2），并将这些与PS联系起来，并寻求鉴定PS的其他生物标志物；2)鉴定s -亚硝基化血浆加合物，这些加合物和其他蛋白质通过炎症、氧化应激和加速凋亡参与黑质纹状体细胞损伤和死亡；3)进行与LPS摄取和毒性相关的靶向基因分型，以及这些相同的PS发病途径（神经炎症、氧化应激和细胞凋亡）和蛋白质s -亚硝基化或进一步氧化。最终，这项研究具有极好的潜力来阐明进一步的PS机制，这些机制可能归因于一种定义明确的常见环境毒物。PS生物标志物的鉴定为疾病预防和早期检测提供了良好的前景，具有明确的转化意义。此外，在三个研究小组之间建立一个联盟应该为未来对PS和其他神经退行性疾病的环境原因的跨学科研究奠定基础。

DESCRIPTION (provided by applicant): This application is to establish a Virtual Consortium for Translational/Transdisciplinary Research (ViCTER) of three research groups engaged in epidemiological, translational and basic science research into environmental causes of parkinsonism (PS), including Parkinson disease (PD). The Consortium's efforts will expand an ongoing epidemiological study of PS among women textile workers in Shanghai exposed to endotoxin (lipopolysaccharide [LPS]). LPS is a widespread environmental inflammagen and very potent experimental inducer of nigrostriatal cell injury and death. In fact, a convincing experimental rodent model of LPS-induced PS recapitulates the pathological features and motor effects seen in humans. Neuroinflammation via indirect microglial activation by pro-inflammatory mediators is the presumed major pathogenesis mechanism of LPS- induced PS. Gram-negative bacteria is the source of LPS, and substantial LPS exposures in the study cohort derive from cotton handling and processing. The investigators have previously quantified LPS exposures among cohort members for ongoing studies of PS and cancer. The aims of the parent project (R01E5017462), directed by Dr. Checkoway, are to estimate dose-response relations of quantified occupational LPS exposures with risk, severity, and progression of clinically validated PS. The new components of the project will be incorporation of peripheral protein and genetic biomarkers that may serve as indicators of risk, further characterization of the LPS mechanistic pathway, and identification of genetic susceptibility factors relevant to the LPS-PS pathway. The aims of this application are to: 1) characterize plasma and saliva biomarkers pertinent to neuroinflammation and oxidative/nitrosative (redox) stress, including cytokines/chemokines, complement 3 (C3), factor H (FH), 1-synuclein, DJ-1 (PARK7), protein disulfide isomerase (PDI), PTEN induced putative kinase 1 (PINK1), ubiquitin carboxyl-terminal esterase L1 (UCHL1), and parkin (PARK2), and to relate those with PS, and seek to identify additional biomarkers of PS; 2) identify S-nitrosylated plasma adducts on these and other proteins involved in nigrostriatal cell injury and death via inflammation, oxidative stress, and accelerated apoptosis; 3) perform targeted genotyping related to LPS uptake and toxicity and these same PS pathogenesis pathways (neuroinflammation, oxidative stress, and apoptosis) and protein S-nitrosylation or further oxidation. Ultimately, this research has excellent potential to elucidate further PS mechanisms potentially attributable to a well-defined common environmental toxicant. Identification of PS biomarkers offers good promise for disease prevention and early detection, which have clear translational implications. Moreover, development of a consortium among the three research groups should lay the groundwork for future transdisciplinary research into environmental causes of PS and other neurodegenerative disorders. PUBLIC HEALTH RELEVANCE: Endotoxin/LPS is a highly plausible cause of human PS, based on accepted animal models. By incorporating biomarker and genotyping components into the parent epidemiological study of PS in Shanghai textile workers exposed to LPS, the investigators will have an excellent opportunity to elucidate further pathogenesis mechanisms and potentially identify high risk persons. Successful completion of this research would have substantial implications for prevention of this relatively common, but highly debilitating condition.