Effects-Related Biomarkers of Environmental Neurotoxic Exposures

项目总结 这项提案是为了对华盛顿大学(UW)超级基金研究中心进行为期5年的竞争性续签 计划(SRP)。该计划的主要主题是调查 金属对人类和水生物种的神经毒性。基于我们的工作，我们正在开发生物标记物 预测：1)暴露于神经毒性药物，2)神经毒性损伤的早期指标 生物水平，和/或3)对环境异常敏感的遗传决定因素 神经毒药。研究中的生理过程对认知、嗅觉和 神经行为过程，并与阿尔茨海默氏症和非阿尔茨海默氏症的风险有关 相关的痴呆症、帕金森氏病和其他神经发育疾病。我们的研究重点是 通常出现在超级基金危险废物场地的金属，这些场地存在重要的数据缺口 妨碍充分了解其对人类健康和水生物种的神经毒性影响。这些数据 差距包括对毒性、个体间或性别易感性的机制的了解，以及 决定它们在环境中命运的生物地球化学因素。我们项目的一个关键主题是解决 细胞氧化应激在金属神经毒性中的作用。UW计划将包括四个 研究项目(两个环境科学和两个生物医学项目)。研究项目包括 (1)太平洋鲑鱼金属嗅觉损伤机制及生物标志物的初步研究 关注镉；(2)镉对啮齿动物神经毒性的细胞和分子机制， 包括对嗅觉和认知的影响；(3)对氧磷酶作为镉和镉的修饰物的作用 城市湖泊系统中砷的生物地球化学和生物可利用性 华盛顿州。我们的项目包括项目和核心之间的协作，每个项目都是 跨学科性质。UW SRP包括一个多学科和跨学科的培训核心，并将 支持参与部门的博士后学员。研究翻译核心将继续 确保及时、适当地将我们的研究结果传达给NIEHS和其他适当的 利益相关者，与机构有效合作，识别潜在专利，开发和支持翻译 与我们的科学发现的其他最终用户的机会。社区参与核心(一个新的核心 从2015年开始提供资金)将建立在现有伙伴关系的基础上，并扩大与其他 社区，例如那些直接受到我们正在研究的毒物影响的社区，以及与其他社区 对环境毒物有顾虑的团体。行政核心将促进互动 在项目和核心之间确保完全的计划整合，确保与NIEHS进行适当的沟通 和其他政府机构，监督人事和预算事项，并组织会议和 与内部执行委员会和外部咨询委员会的互动。

PROJECT SUMMARY This proposal is for a 5-year competing renewal of the University of Washington (UW) Superfund Research Program (SRP). The overarching theme of the program is to investigate the mechanisms and ramifications of metal neurotoxicity in humans and aquatic species. Based upon our work, we are developing biomarkers predictive of; 1) exposure to neurotoxic agents, 2) early indicators of neurotoxic injury at the cellular and organismal levels, and/or 3) genetic determinants that underlie unusual susceptibility to environmental neurotoxicants. The physiological processes under investigation adversely affect cognition, olfaction and neurobehavioral processes, and are associated with the risk of developing Alzheimer's and non-Alzheimer's related dementia, Parkinson's disease, and other neurodevelopmental diseases. Our research focuses upon metals that commonly occur at Superfund hazardous waste sites for which there are important data gaps impeding the full understanding of their neurotoxic effects on human health and aquatic species. These data gaps include an understanding of mechanisms of toxicity, inter-individual or gender susceptibility, and biogeochemical factors that govern their fate in their environment. A key theme of our projects is addressing the role of cellular oxidative stress during metal-induced neurotoxicity. The UW program will include four research projects (two environmental science and two biomedical projects). The research projects include investigations of (1) mechanisms and biomarkers of metal olfactory injury to Pacific salmon, with a primary focus on cadmium; (2) cellular and molecular mechanisms of cadmium-mediated neurotoxicity in rodents, including effects on olfaction and cognition; (3) the role of paraoxonases as modifiers of cadmium and manganese neurotoxicity; and (4) biogeochemistry and bioavailability of arsenic in an urbanized lake system in Washington State. Our projects include collaborations among projects and cores, and each project is interdisciplinary in nature. The UW SRP includes a Training Core that is multi- and interdisciplinary, and will support predoctoral trainees from participating departments. The Research Translation Core will continue to ensure timely and appropriate communication of our research findings to NIEHS and other appropriate stakeholders, partner effectively with agencies, identify potential patents, and develop and support translation opportunities with other end-users of our scientific findings. The Community Engagement Core (a new Core beginning with 2015 funding) will build upon existing partnerships and expand partnerships with other communities, such as those directly affected by the toxicants we are studying, and with other community groups that have concerns about environmental toxicants. The Administrative Core will stimulate interactions among projects and cores ensuring full program integration, assure appropriate communication with NIEHS and other governmental agencies, oversee personnel and budgetary matters, and organize meetings and interactions with the Internal Executive Committee and the External Advisory Board.