Effects-Related Biomarkers of Environmental Neurotoxic Exposures

这项提案是对华盛顿大学(UW)超级基金基础研究计划项目进行为期5年的竞争性续签。该计划的主题是，在可接触的组织中测量的生物标记物可以预测：a)有毒物质暴露；b)损害的早期指标；和/或c)超级基金地点常见的对有毒物质的异常易感性。拟议的UW计划包括5个研究项目(3个生物医学项目，2个非生物医学项目[生态毒理学，生物修复])，其中2个是新的(都是生物医学项目)。该计划将最集中地关注生物标记物的应用，以调查神经毒性化学品(主要是金属和杀虫剂)对人类健康和环境的不利影响。总的来说，这些项目将为以下方面开发和验证生物标记物：阐明人类和动物模型中潜在的神经毒性机制；识别人类早期的神经疾病过程；使用PS作为模型结果，表征选定的神经毒物与神经疾病风险、严重程度和进展的剂量-反应关系；以及实施植物修复技术。研究项目包括：1)有机磷农药敏感性动物模型，应用于接触农药的农场工人和帕金森氏症患者；2)专业焊工中的金属与帕金森氏症；3)金属诱导PS的蛋白质组标记；4)自由生活的Coho鲑鱼中金属和农药的亚致死神经毒性作用；以及5)有机溶剂和农药的植物修复方法。行政核心将监督方案的所有预算和报告方面，并将促进项目和核心之间的多学科互动。功能基因组学和生物信息学核心将为所有研究项目提供广泛的分子生物学实验室和数据分析支持。研究翻译核心将确保将我们的研究结果及时和适当地传达给相关利益攸关方，包括政府机构、社区团体和私营部门。

This proposal is for a 5-year competing renewal of the University of Washington (UW) Superfund Basic Research Program Project. The theme of this program is that biomarkers measured in accessible tissues are predictive of: a) toxicant exposures; b) early indicators of damage; and/or c) unusual susceptibility to toxic agents that commonly occur at Superfund sites. The proposed UW Program includes 5 research projects (3 biomedical, 2 non-biomedical [ecotoxicology, bioremediation]), 2 of which are new (both biomedical). The program will focus most intensively on biomarker applications for investigations of adverse effects to human health and the environment from neurotoxic chemicals, primarily metals and pesticides. Collectively, these projects will develop and validate biomarkers for: elucidating underlying neurotoxicity mechanisms in humans and animal models; identifying early-stage neurologic disease processes in humans; characterizing dose-response relations for selected neurotoxicants with neurologic disease risk, severity, and progression, using PS as a model outcome; and, for implementing phytoremediation techniques. The research projects include studies of: 1) animal models of susceptibility to organophosphate pesticides, with applications to pesticide-exposed farmworkers and to persons affected with Parkinson's disease; 2) metals and Parkinsonism among professional welders; 3) proteomic markers of metal-induced PS; 4) sub-lethal neurotoxic effects of metals and pesticides in free-living Coho salmon; and, 5) phytoremediation methods for organic solvents and pesticides. The Administrative Core will oversee all budgetary and reporting aspects of the Program, and will foster multidisciplinary interactions among projects and cores. The Functional Genomics and Bioinformatics Core will provide extensive molecular biology laboratory and data analysis support to all research projects. The Research Translation Core will ensure timely and appropriate communication of our research findings to relevant stakeholders, including government agencies, community groups, and the private sector.