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 - 锌调节铀和砷免疫失调

• 批准号: 9903354
• 负责人: Debra MacKenzie
• 金额: $ 25.24万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9903354
• 关键词: Address; Adverse effects; Antinuclear Antibodies; Archives; Arsenic; Autoimmune Process; Autoimmunity; Back; Biological Models; Biological Monitoring; Biometry; Blood; Cardiovascular Diseases; Cell model; Cells; Chronic; Chronic Disease; Communities; Cross-Sectional Studies; DNA Damage; Data; Detection; Development; Dietary Zinc; Experimental Models; Exposure to; Goals; Health; Human; IL17 gene; Immune; Immune response; Immunologic Markers; Immunologics; In Vitro; Individual; Information Systems; Interleukin-4; Intervention; Intervention Trial; Investigation; Kidney Diseases; Laboratories; Lymphocyte; Measurement; Measures; Mediating; Metabolic Diseases; Metal exposure; Metals; Mining; Mus; Native Americans; Navajo; New Mexico; Outcome Measure; Outcome Study; Pathway Analysis; Peripheral Blood Mononuclear Cell; Phenotype; Population; Predisposition; Production; Proteins; Publishing; Pueblo Race; Reporting; Research; Research Personnel; Research Support; Risk; Sampling; Serum; Signal Recognition Particle; Site; Splenocyte; Superfund; TNF gene; Tertiary Protein Structure; Testing; Toxic effect; Translational Research; Universities; Uranium; Urine; Work; Zinc; Zinc supplementation; base; cellular targeting; cytokine; data management; dietary supplements; immune function; immunoregulation; immunotoxicity; improved functioning; in vivo; innovation; lymphocyte proliferation; member; metal complex; metal poisoning; molecular marker; mouse model; novel; programs; protein function; tribal community; tribal lands; ubiquitin-protein ligase; wasting; zinc-binding protein

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.

项目3 - 生物医学项目1（BP1） - 摘要 与美国原住民社区合作，对部落的金属暴露和毒性评估 西南（UNM金属）团队的土地已获得社区层面暴露和 与1100多个废弃的铀矿（AUM）废物相关的健康风险。 该项目将解决有关免疫失调的潜在机制，包括早期 自身免疫的分子标记，与AUM和铀和混合金属暴露有关。 生物监测结果证实，社区成员暴露于铀和其他金属之外 国家规范。我们发布的初步工作表明，某些金属与关键细胞靶标相互作用 破坏依赖锌的蛋白质功能。我们将检验以下假设，即金属破坏了多个类别 锌结合蛋白已知可调节免疫呼吸的蛋白质，该补充锌会减轻 金属暴露引起的免疫毒性。在AIM 1目标中，我们将调查血清锌足够是否足够 通过执行横截面，修饰暴露于环境金属的个体中的免疫失调 分析存档的人口样本，用于免疫功能与金属和金属标记之间的关联和 血液和尿液样品中存在锌水平。 AIM 2将测试免疫毒性作用和基础 U的机制，AS和环境相关的金属混合物，由环境项目定义，以及 在细胞和小鼠模型中补充锌会降低免疫毒性作用。 AIM 3将测试 饮食锌补充是否会降低暴露的免疫失调的生物标志物 人口与暴露的社区合作。这项工作是通过结合曝光而创新的 来自实验模型中的机械研究的信息和生物监测数据。 迄今为止，还没有重要的，基于社区的健康研究来描述暴露和免疫学 这些受影响部落社区的结果措施。我们提出了一个新的假设，即金属 暴露破坏对免疫功能至关重要的多种类别的Zn结合蛋白导致免疫功能 失调和补充锌会减轻金属毒性。这项研究代表了第一个人 基于补充锌的干预来改善混合金属暴露的不利影响。到 实现研究目标，BP1与环境项目充分融合，以告知不同的金属 暴露，BP2共享机械数据和模型系统，社区参与和研究 社区投入和报告结果的核心核心，以及生物统计学和生物统计学和 研究支持的数据管理核心。这些研究的结果将通过测试很重要 社区关注的金属和金属混合物，以阐明对免疫的影响和机制 在暴露人群中检测到的失调，并测试基于机制的干预的可行性 减轻金属暴露的不利影响。