Project 2: Parkinsonism and Metal Exposures Among Welders

项目2，这将是新的UW SBRP，是一个流行病学调查的作用，金属作为决定因素的风险，严重程度和帕金森病（PS）的专业焊工。以前的流行病学和实验研究表明，锰（Mn）和其他金属，单独和组合，和PS之间的联系非常合理。研究人群包括875名威斯康星州造船厂焊工（775名在职人员，100名退休人员）和200名非暴露的造船厂焊工 无焊接暴露史的工人先前参加了正在进行的NEIHS资助的R 01（ES 013743; PI：B。Racette;共同研究者：H. Checkoway，N. Seixas）。这项拟议研究的新特点是改进暴露评估，以产生定量的金属特异性水平，并重复神经系统检查PS相关运动功能的纵向变化。该项目的科学目标是：1）估计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）测试这些金属暴露与PS进展相关的假设; 3）确定PS蛋白质组学生物标志物的预测关系，在项目3中进行了表征（Zhang博士），与PS风险，严重程度和进展; 4）测试Mn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，我们将在入组检查后3年对尽可能多的研究受试者（约75%）进行重复的运动功能标准化神经学检查（统一帕金森病评定量表运动子部分3 [APRS 3]）。此外，与项目3合作，我们将收集血浆样本，用于蛋白质组学分析，这些蛋白质组学分析已被验证为与根据基线CRISPR 3（“正常”、临界PS、可能/明确PS）选择的150例受试者样本的PS强相关性。将通过问卷调查获得潜在重要混杂因素的数据，特别是吸烟和农药暴露。该项目具有很大的潜力，可以量化金属对神经系统的影响程度，金属是广泛的环境污染物，因此可以有助于疾病预防策略。

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.