ENVIRONMENTAL/GENETIC RISK FACTORS FOR PARKINSON'S

帕金森病的环境/遗传风险因素

• 批准号: 6518194
• 负责人: JORDAN A FIRESTONE
• 金额: $ 12.56万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6518194
• 关键词: Parkinson's disease; amine oxidase (flavin); clinical research; cytochrome P450; disease /disorder etiology; dopamine; environmental toxicology; enzyme activity; enzyme linked immunosorbent assay; gene environment interaction; genetic polymorphism; genetic susceptibility; glutathione transferase; human genetic material tag; human population genetics; human subject; interview; longitudinal human study; neurotransmitter metabolism; nucleic acid sequence; passive smoking; pesticides; polymerase chain reaction; serotonin; solvents

My immediate career goal is to establish a patient-oriented research program on Parkinson's disease (PD) while completing a Master of Public Health. My long-term goal is to apply my various skills in clinical neurology, experimental pharmacology, and epidemiological research to address questions regarding the interactions between the environment and genetics in the development of neurological disease. I anticipate doing this in an academic environment with the opportunity for ongoing and close collaboration between disciplines, as represented in this proposal. The focus of my intermediate career goals is understanding the etiology of PD. Evidence suggests that PD results from an interaction between environmental exposures to particular toxins and genetic factors that act as effect modifiers or independent risk factors. Current efforts to understand these interactions rely on the combined techniques of analytic epidemiology and molecular biology. This proposal will couple these approaches with clinical neurological assessment in order to elucidate these interactions. The first aim is to use a population-based, case-control study of PD to evaluate genetic polymorphisms as possible effect modifiers of environmental exposures. DNA samples will be analyzed for genetic polymorphisms related to dopamine and xenobiotic metabolism (MAO- B, CYP-2D6 and 2E1, PON1, and GST isoenzymes Ml, T1, and P1). The second aim will extend this ongoing study to include cases of drug-induced parkinsonism (DIP), based on the hypothesis that if these cases represent a group of especially susceptible patients, they may harbor genetic polymorphisms of interest. The third aim will be to use an ongoing longitudinal, cohort study of orchardists evaluating the association of parkinsonism with historic, chronic pesticide exposures. In this work I will utilize my previous training in clinical neurology to provide increased internal validity and decrease the effect of disease misclassification. As well, models to refine individual exposure assessments will be developed and applied to historic data in order to decrease the effect of exposure misclassification. The fourth aim will be to evaluate the role of the alpha-7 nicotinic receptor as a risk factor for PD. I will benefit from direct mentoring by national leaders in the fields of Environmental Health and Epidemiology (Dr. Checkoway), Neurology (Dr. Longstreth), and Occupational Medicine (Dr. Keifer). My aims will extend and augment the ongoing, multidisciplinary investigation of PD risk factors, while providing me an unparalleled opportunity to develop my career in the rich, scientific milieu of the University of Washington.

我的直接职业目标是在完成公共卫生大师时建立一个面向患者的研究计划（PD）。 我的长期目标是将我的各种技能应用于临床神经病学，实验药理学和流行病学研究，以解决有关神经系统疾病发展环境与遗传学之间相互作用的问题。 我希望在学术环境中这样做，并有机会在学科之间进行持续和密切的合作，如本提案所示。 我中级职业目标的重点是了解PD的病因。 有证据表明，PD是由于环境暴露于特定毒素和充当影响修饰符或独立危险因素的遗传因素之间的相互作用而引起的。 当前了解这些相互作用的努力取决于分析流行病学和分子生物学的组合技术。 该建议将这些方法与临床神经系统评估相结合，以阐明这些相互作用。 第一个目的是使用PD的基于人群的病例对照研究来评估遗传多态性的环境暴露的效果修饰符。 DNA样品将分析与多巴胺和异种代谢有关的遗传多态性（Mao-B，CYP-2D6和2E1，PON1和GST Isoenzymes ML，T1和P1）。第二个目的将扩展这项正在进行的研究，以包括药物诱导的帕金森氏症（DIP）病例，这是基于以下假设：如果这些病例代表了一组特别易感的患者，则可能具有感兴趣的遗传多态性。 第三个目的是利用正在进行的纵向同伴研究，该研究评估了帕金森主义与历史悠久的长期农药暴露的关联。 在这项工作中，我将利用我以前的临床神经病学培训来提供内部有效性的提高并减少疾病错误分类的影响。 同样，将开发完善个人暴露评估的模型，并将其应用于历史数据，以减少暴露效果错误分类。 第四个目标是评估α-7烟碱受体作为PD的危险因素的作用。我将受益于环境健康和流行病学领域的国家领导人（Checkoway博士），神经病学（Longstreth博士）和职业医学（Keifer博士）的直接指导。 我的目标将扩展和扩大对PD风险因素的持续多学科调查，同时为我提供了一个无与伦比的机会，可以在华盛顿大学的富裕，科学环境中发展自己的职业。