Effects-Related Biomarkers of Environmental Neurotoxic Exposures

 描述(由申请人提供)：这项建议的中心拨款申请是为华盛顿大学超级基金研究计划(SRP)的5年竞争性续签(A1)。该计划的主要主题是研究金属神经毒性在人类和水生物种中的机制和影响，并在此基础上开发生物标记物。这些生物标志物可以预测(A)暴露于神经毒物，(B)细胞和生物水平的神经毒性损伤的早期指标，和/或(C)环境神经毒物异常易感性的遗传决定因素。重点是金属神经毒性，包括那些经常出现在超级基金危险废物场地的金属，对于这些金属，有重要的数据空白，阻碍了对其对人类和生态健康的影响的充分了解。这些数据差距包括对毒性机制、个体间或性别易感性以及决定其环境命运的生物地球化学因素的理解。该计划将包括五个研究项目(两个环境科学项目和三个生物医学项目)，其中一个(项目2)是我们自2013年提交A0以来的一个新的生物医学项目。这项研究包括以下方面：(1)金属嗅觉伤害太平洋鲑鱼的机制和生物标志物，主要集中在Cd；(2)Cd介导的啮齿动物和人类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Cd，Mn修饰物的作用和农药在动物模型和人类中的神经毒性；(4)南非社区生活在冶炼厂附近的环境暴露对嗅觉、运动和认知的影响；(5)华盛顿州城市化湖泊系统中As的生物地球化学和生物有效性。根据战略行动方案的战略目标和对2013年审查的回应，该小组保留了海军陆战队战略行动方案的优势和主题，同时对薄弱环节进行了实质性修改。这些项目包括与其他项目和核心的关键合作伙伴，因此每个项目都是跨学科的。该计划包括一个多学科和跨学科的培训核心，将支持博士前实习生。研究翻译核心将继续确保将我们的研究成果及时和适当地传达给NIEHS和其他适当的利益相关者，有效地与机构合作，识别潜在的专利，并与我们科学发现的其他最终用户开发和支持翻译机会。社区参与核心将建立在现有伙伴关系的基础上，并扩大与其他社区的伙伴关系，例如那些直接受到研究中的毒物影响的社区，以及与其他关注环境毒物的社区团体的伙伴关系。行政核心将促进项目和核心之间的互动，确保与NIEHS和其他政府机构的沟通，监督人事和预算事项，并组织与外部咨询委员会的会议和互动。

 DESCRIPTION (provided by applicant): This proposed Center grant application is for a 5-year competing renewal (A1) of the University of Washington 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, and develop biomarkers based upon this understanding. These biomarkers may be predictive of (a) exposures to neurotoxic agents, (b) early indicators of neurotoxic injury at the cellular and organismal levels, and/or (c) genetic determinants that underlie unusual susceptibility to environmental neurotoxicants. The focus is on metal neurotoxicity, including those metals that commonly occur at Superfund hazardous waste sites for which there are important data gaps impeding the full understanding of their effects on human and ecological health. These data gaps include an understanding of mechanisms of toxicity, inter-individual or gender susceptibility, and biogeochemical factors that govern their environmental fate. The program will include five research projects (two environmental science and three biomedical projects), one of which (Project 2) is a new biomedical project since our 2013 A0 submission. The research includes investigations of (1) mechanisms and biomarkers of metal olfactory injury to Pacific salmon, with a primary focus on Cd; (2) cellular and molecular mechanisms of Cd-mediated neurotoxicity in rodents and humans, including effects on olfaction and cognition; (3) the role of paraoxonases as modifiers of Cd, Mn, and pesticide neurotoxicity in animal models and humans; (4) olfactory, motor, and cognitive effects from environmental exposure to manganese in a South African community living near a smelter; and (5) biogeochemistry and bioavailability of As in an urbanized lake system in Washington State. In accordance with the strategic goals of the SRP and in response to the 2013 reviews, this team has retained the strengths and theme of the UW SRP while making substantive changes to address weaknesses. The projects include key collaborators with other projects and cores, and thus each project is interdisciplinary in nature. The program includes a Training Core that is multi- and interdisciplinary, and will support pre-doctoral trainees. 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 will build upon existing partnerships and expand partnerships with other communities, such as those directly affected by the toxicants under study, and with other community groups that have concerns about environmental toxicants. The Administrative Core will stimulate interactions among projects and cores, ensure communication with NIEHS and other governmental agencies, oversee personnel and budgetary matters, and organize meetings and interactions with the External Advisory Board.