ENVIRONMENTAL AND BIOCHEMICAL RISK FACTORS FOR PARKINSON'S DISEASE

帕金森病的环境和生化风险因素

• 批准号: 6666385
• 负责人: Harvey Checkoway
• 金额: $ 22.2万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6666385
• 关键词: Parkinson's disease; amine oxidase (flavin); biomarker; clinical research; cytochrome P450; disease /disorder etiology; disease /disorder proneness /risk; environmental exposure; environmental health; environmental toxicology; gene environment interaction; gene expression; genetic polymorphism; genetic susceptibility; genotype; glutathione transferase; hazardous substances; heavy metals; human subject; nervous system disorder epidemiology; oxidative stress; pesticides; solvents; superoxide dismutase

Parkinson's disease (PD) is a chronic neurodegenerative disorder that affects millions of persons worldwide.. The etiology of PD remains largely unexplained. There is, however, increasing experimental and epidemiologic evidence that environmental toxicants, including those commonly found at hazardous waste sites, are etiologically related to the development of PD. Recent thinking on PD causation also emphasizes the significance of gene/environment interactions, whereby persons who carry genotypes predictive of either a diminished capacity for chemical detoxification or enhanced propensity to activate pro-neurotoxicants are most susceptible to environmentally-induced PD. We are proposing to extend our ongoing population-based case-control study which is investigating the effects of environmentally and genotypic risk factors, and their interactions, on risk of PD. The target goal of the study will be 400 newly diagnosed idiopathic PD cases and 6500 age. gender/race- matched controls free of PD and other major neurodegenerative disorders. Study subjects are identified from a defined population source, Group Health Cooperative of Puget Sound, Washington. Exposures of greatest a priori interest are industrial solvents, heavy metals, and pesticides. We will also investigate the unique and interactive associations of known polymorphisms of genes encoding enzymes pertinent to environmental chemical activation and/or detoxification, including: type B monoamine oxidase (MAO-BN), cytochromes P450 (CYP) 2D6 and 2E1, and the M1, T1, and P1 isozymes of glutathione S-transferase (GST). A unifying hypothesis of PD pathogenesis underlying this research is that chemical that provoke oxidative stress reactions destroy dopaminergic neurons preferentially among persons with unknown genetic polymorphisms of MAO-B and GSTM. In addition, we will conduct a series of in vitro experiments to determine the functional significance of several MAO-B and GST polymorphisms to characterize further mechanistic relations with PD pathogenesis. Direct interactions are planned between this study and projects 3 (Dr. Costa) and 4 (Dr. Keiffer) that also address environmentally-related neurotoxicity. Insofar the causation of PD remains elusive, this investigation will generate important new scientific and public health knowledge. Furthermore, this project may ultimately serve as model approach for investigating the complex interplay between low-level environmental exposures, as would be anticipated to result from hazardous waste sites, and host factors on risk for neurodegenerative disorders.

帕金森氏病（PD）是一种慢性神经退行性疾病，影响了全球数百万的人。PD的病因在很大程度上无法解释。但是，有越来越多的实验性和流行病学证据表明，环境毒物（包括在危险废物地点通常发现的）与PD的发展有关。关于PD因果关系的最新思考还强调了基因/环境相互作用的重要性，这些人携带基因型的人可以预测化学解毒能力降低或激活促启发性神经毒素的倾向降低，这对环境诱发的PD最容易受到影响。我们建议扩展我们正在进行的基于人群的病例对照研究，该研究正在研究环境和基因型危险因素及其相互作用对PD风险的影响。该研究的目标目标是400个新诊断的特发性PD病例和6500年龄。性别/种族匹配的控件没有PD和其他主要神经退行性疾病。研究对象是从华盛顿普吉特海湾的群体健康合作社确定的。先验兴趣最大的暴露是工业溶剂，重金属和农药。我们还将研究编码与环境化学化学激活和/或排毒酶的基因的已知多态性的独特和互动关联，包括：B型单胺氧化酶（MAO-BN），细胞色素P450（CYP）2d6和2e1，以及M1，T1，T1，T1，T1，P1和P1 g1 glut gluttrutclate（CYP）2d6和2e1（CYP）2d6和2e1，这项研究基础的PD发病机理的统一假设是，在MAO-B和GSTM的遗传多态性未知的人中优先破坏了氧化应激反应的化学物质。此外，我们将进行一系列体外实验，以确定几种MAO-B和GST多态性的功能意义，以表征与PD发病机理的进一步机械关系。这项研究与项目3（Costa博士）和4（Keiffer博士）之间进行了直接互动，这些互动也解决了与环境有关的神经毒性。在PD的因果关系仍然难以捉摸的情况下，这项调查将产生重要的新科学和公共卫生知识。此外，该项目最终可能是研究模型方法，用于研究低级环境暴露之间的复杂相互作用，这将是由于危险废物站点和神经退行性疾病风险的宿主因素所预期的。