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(BP1)--摘要 与美洲原住民社区合作，UNM对部落的金属暴露和毒性评估 西南土地(UNM Metals)小组已获得社区一级暴露的证据，并 与部落土地上1100多个废弃铀矿废弃场有关的健康风险。 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，与接近AUM和铀以及混合金属暴露有关。 生物监测结果证实，社区成员暴露在铀和其他金属之外 国家标准。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 扰乱锌依赖的蛋白质功能。我们将检验这样一种假设，即金属破坏了多种类别的 已知的锌结合蛋白调节免疫反应，补充锌将缓解 金属暴露引起的免疫毒性。在目标1中，我们将调查血清锌是否充足 通过进行横断面实验改善暴露于环境金属的个体的免疫失调 人群样本中免疫功能标志物与金属元素的相关性分析 血液和尿液样本中的锌含量。目标2将测试免疫毒性效应和潜在的 环境项目定义的铀、砷和与环境有关的金属混合物的作用机理；以及 在细胞和小鼠模型中补充锌是否降低了免疫毒性作用。AIM 3将测试 膳食补锌是否会降低暴露人群免疫失调的生物标志物 与受感染社区结成伙伴关系的人口。这部作品结合了曝光的特点，具有创新性 暴露人群的信息和生物监测数据与实验模型中的机理研究。 到目前为止，还没有以社区为基础的重大健康研究同时描述暴露和免疫学 在这些受影响的部落社区中衡量结果。我们提出了一个新的假设，即金属 暴露扰乱了多种锌结合蛋白，这些结合蛋白对免疫功能至关重要，导致免疫 调节失调，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。至 实现研究目标，BP1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、共享机械数据和模型系统的BP2、社区参与和研究 用于社区输入和向社区报告结果的翻译核心，以及生物统计和 用于研究支持的数据管理核心。通过测试，这些研究的结果将是有意义的 社区关注的金属和金属混合物，以阐明免疫的影响和机制 在暴露人群中检测到的调节失调，并测试基于机制的干预的可行性 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.