Endotoxin Exposure and Risk of Parkinsonism

描述（由申请人提供）：本申请旨在建立一个转化/跨学科研究虚拟联盟（ViCTER），由三个研究小组组成，从事帕金森综合征（PS）（包括帕金森病（PD））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流行病学研究PS在上海纺织女工暴露于内毒素（脂多糖[LPS]）。LPS是一种广泛存在的环境致炎因子，是黑质纹状体细胞损伤和死亡的非常有效的实验诱导剂。事实上，一个令人信服的实验啮齿动物模型的LPS诱导PS概括的病理特征和运动的影响，在人类中看到的。通过促炎介质间接激活小胶质细胞引起的神经炎症是LPS诱导PS的主要发病机制。革兰氏阴性菌是LPS的来源，研究队列中大量的LPS暴露来自棉花处理和加工。研究人员先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（R 01 E5017462）的目的是估计定量职业LPS暴露与临床验证PS的风险、严重程度和进展的剂量-反应关系。该项目的新组成部分将是纳入外周蛋白和遗传生物标志物，可作为风险指标，进一步表征LPS机制途径，并鉴定与LPS-PS途径相关的遗传易感性因素。本申请的目的是：1）表征与神经炎症和氧化/亚硝化（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（PARK 7）、蛋白质二硫键异构酶（PDI）、PTEN诱导的推定激酶1（PINK 1）、泛素羧基末端酯酶L1（UCHL 1）和parkin（PARK 2），2）鉴定这些和其它蛋白质上的S-亚硝基化血浆加合物，所述蛋白质参与通过炎症、氧化应激和加速凋亡的黑质纹状体细胞损伤和死亡; 3）进行与LPS摄取和毒性以及这些相同的PS发病途径相关的靶向基因分型（神经炎症、氧化应激和凋亡）和蛋白S-亚硝基化或进一步氧化。最终，这项研究具有很好的潜力，进一步阐明PS机制可能归因于一个明确的共同环境毒物。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，这具有明确的翻译意义。此外，三个研究小组之间的联盟的发展应该为未来的跨学科研究PS和其他神经退行性疾病的环境原因奠定了基础。 公共卫生相关性：根据公认的动物模型，内毒素/LPS是人类PS的一个非常合理的原因。通过将生物标志物和基因分型成分纳入上海纺织工人暴露于LPS的PS母流行病学研究，研究者将有很好的机会阐明进一步的发病机制，并可能识别高危人群。这项研究的成功完成将对预防这种相对常见但高度衰弱的疾病产生重大影响。

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.