Project 3 - Biomedical Project 1 - BP1 - Modulation of Uranium and Arsenic Immune Dysregulation by Zinc

项目3 -生物医学项目1（BP 1）-总结 通过与美洲原住民社区合作，UNM部落金属接触和毒性评估 西南地区（UNM金属）团队已经获得了社区水平暴露的证据， 他们的部落土地上有1100多个废弃的铀矿（AUM）废物场。 该项目将解决免疫失调的潜在机制，包括早期 自身免疫的分子标志物，与AUM和铀及混合金属暴露的接近度相关。 生物监测结果证实，社区成员暴露于铀和其他金属， 国家规范。我们发表的和初步的工作表明，某些金属与关键的细胞靶点相互作用， 破坏锌依赖蛋白的功能我们将测试金属破坏多种类型的 已知锌结合蛋白可以调节免疫反应，补充锌可以减轻免疫反应 金属接触导致的免疫毒性。目的1：探讨血清锌是否充足 通过进行横断面研究， 分析存档人群样本中免疫功能标志物与金属和 血液和尿液样本中的锌含量。目的2将测试免疫毒性作用和潜在的 环境项目规定的铀、砷和与环境有关的金属混合物的机制，以及 在细胞和小鼠模型中补充锌是否降低免疫毒性作用。目标3将测试 膳食锌补充是否会降低暴露于锌的儿童免疫失调的生物标志物 与受影响社区合作。这件作品是创新的， 通过在实验模型中进行机理研究，从接触人群中收集信息和生物监测数据。 到目前为止，还没有显著的，以社区为基础的健康研究描述暴露和免疫学 在这些受影响的部落社区的成果措施。我们提出了一个新的假设， 暴露破坏了对免疫功能至关重要的多种Zn结合蛋白， 补充锌将减轻金属毒性。这项研究代表了第一个人类 以补锌为基础的干预措施，以减轻混合金属暴露的不良影响。到 为了实现研究目标，BP 1与环境项目很好地结合在一起，为不同的金属提供信息 暴露，BP 2共享机械数据和模型系统，社区参与和研究 翻译核心，用于社区输入和向社区报告结果，以及生物统计和 用于研究支持的数据管理核心。这些研究的结果将通过测试 社区关注的金属和金属混合物，以阐明对免疫系统的影响和机制 在暴露人群中检测到的失调，并测试基于机制的干预措施的可行性， 减轻金属暴露的不利影响。

PROJECT 3 – BIOMEDICAL PROJECT 1 (BP1) - SUMMARY With partnering Native American communities, the UNM Metals Exposure and Toxicity Assessment on Tribal Lands in the Southwest (UNM METALS) team has obtained evidence for community level exposures and health risks associated with more than 1100 abandoned uranium mine (AUM) waste sites on their tribal lands. This project will address underlying mechanisms to account for immune dysregulation, including early molecular markers of autoimmunity, associated with proximity to AUM and uranium and mixed metal exposure. Biomonitoring results confirm that community members are exposed to uranium and other metals beyond national norms. Our published and preliminary work shows that certain metals interact with key cellular targets to disrupt zinc-dependent protein function. We will test the hypothesis that metals disrupt multiple classes of zinc binding proteins known to regulate immune responses, and that supplemental zinc will mitigate immunotoxicity resulting from metal exposures. In Aim 1 aim we will investigate whether serum zinc sufficiency modifies immune dysregulation in individuals exposed to environmental metals by performing a cross-sectional analysis of archived population samples for associations between markers of immune function with metal and zinc levels present in blood and urine samples. Aim 2 will test the immunotoxic effects and underlying mechanisms of U, As and environmentally relevant metal mixtures defined by the Environmental Projects, and whether the immunotoxic effects are reduced by supplemental zinc in cell and mouse models. Aim 3 will test whether dietary zinc supplementation will decrease biomarkers of immune dysregulation in exposed populations in partnership with exposed communities. The work is innovative by combining exposure information and biomonitoring data from exposed populations with mechanistic studies in experimental models. To date, there are no significant, community-based health studies describing both exposure and immunologic outcome measures in these impacted Tribal communities. We propose a novel hypothesis that metals exposures disrupt multiple classes of Zn binding proteins critical for immune function leading to immune dysregulation and that supplemental Zn will mitigate metal toxicity. This study represents the first human intervention based on zinc supplementation to ameliorate the adverse effects of mixed metal exposures. To achieve the research goals, BP1 is well integrated with the Environmental Projects to inform distinct metals exposures, BP2 to share mechanistic data and model systems, the Community Engagement and Research Translation Cores for community input and reporting results back to the communities, and the Biostatistics and Data Management Core for research support. The outcomes from these studies will be significant by testing metals and metals mixtures of concern to communities to elucidate impact on and mechanisms of immune dysregulation as detected in exposed populations, and test the feasibility of a mechanism-based intervention to alleviate the adverse effects of metals exposures.