Project 2: Parkinsonism and Metal Exposures Among Welders

项目2将是UW SBRP的新项目，是一项关于金属作为专业焊工帕金森氏症(PS)风险、严重程度和进展决定因素的流行病学调查。先前的流行病学和实验研究已经证明，锰和其他金属，无论是单独的还是组合的，与多发性硬化之间存在非常可信的联系。研究人群包括875名威斯康星州造船厂焊工(775名在职焊工，100名退休工人)和200名非暴露的造船厂 以前没有焊接暴露史的工人参加了由NEIHS资助的正在进行的R01(ES013743；PI：B.Racete；联合调查员：H.Checkoway，N.Seixas)。这项拟议研究的新特点将是改进暴露评估以产生定量的金属特异性水平，以及重复神经学检查PS相关运动功能的纵向变化。该项目的科学目标是：1)评估锰和其他金属暴露与PS风险和严重程度之间的剂量-反应关系；2)检验这些金属暴露与PS进展相关的假设；3)确定PS蛋白质组生物标记物的预测关系，如项目3(张博士)所描述的那样，与PS的风险、严重程度和进展；4)测试锰和其他金属的剂量-反应关系，PS蛋白质组生物标志物谱作为临床前疾病的指标。为了实现这些目标，我们将在招生考试后3年对尽可能多的研究对象(~75%)进行重复的标准化神经运动功能检查(统一帕金森氏病评定量表运动部分3[UPDRS3])。此外，我们将与项目3合作，收集根据基线UPDRS3选择的150名受试者的血浆样本，用于蛋白质组学分析，这些样本已被证实与PS密切相关(‘正常’、临界PS、可能/确定的PS)。有关潜在重要混杂因素的数据，特别是吸烟和接触杀虫剂的数据，将通过问卷调查获得。这个项目有很大的潜力来量化金属对神经的影响程度，因为金属是广泛存在的环境污染物，因此可能有助于疾病预防战略。

Project 2, which will be new to the UW SBRP, is an epidemiologic investigation of the roles of metals as determinants of the risk, severity, and progression of parkinsonism (PS) among professional welders. Previous epidemiologic and experimental research has demonstrated very plausible links between manganese (Mn) and other metals, individually and in combination, and PS. The study population includes 875 Wisconsin shipyard welders (775 actively employed, 100 retired) and 200 non-exposed shipyard workers with no welding exposure history previously enrolled in an ongoing NEIHS-funded R01 (ES013743; PI: B. Racette; Co-investigators: H. Checkoway, N. Seixas). The new features of this proposed study will be the refinement of exposure assessment to generate quantitative metal-specific levels, and repeated neurological examinations of longitudinal change of PS-related motor function. The scientific objectives of the project are to: 1) estimate dose-response relations between Mn and other metal exposures and PS risk and severity; 2) test the hypothesis that these metal exposures are associated with PS progression; 3) determine the predictive relations of PS proteomic biomarkers, characterized in Project 3 (Dr. Zhang), with PS risk, severity, and progression; 4) test dose-response relations for Mn and other metals with PS proteomic biomarker profiles as indicators of preclinical disease. To achieve these objects, we will perform repeated standardized neurological exams of motor function (Unified Parkinson's Disease Rating Scale Motor Subsection 3 [UPDRS3]) 3 years after enrollment exams for as many study subjects as can be enrolled (~75%). Addionally, in collaboration with Project 3, we will collect plasma samples for assays of proteomics that have been validated as strongly associated with PS for a sample of 150 subjects selected according to baseline UPDRS3 ('normal', borderline PS, probable/definite PS). Data on potentially important confounding factors, especially cigarette smoking and pesticide exposure, will be obtained by questionnaire. This project has great potential to quantify the extent of neurological effects of metals, which are widespread environmental contaminants, and thus could contribute to disease prevention strategies.