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，新墨西哥州部落金属暴露和毒性评估 西南土地 (UNM METALS) 团队已获得社区层面暴露的证据， 与部落土地上 1100 多个废弃铀矿 (AUM) 废物场相关的健康风险。 该项目将解决免疫失调的潜在机制，包括早期免疫失调 自身免疫的分子标记，与 AUM 和铀以及混合金属暴露的接近程度相关。 生物监测结果证实，社区成员暴露于铀和其他金属之外 我们已发表的初步工作表明某些金属与关键细胞靶标相互作用。 我们将测试金属会破坏多种类型的蛋白质的假设。 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 在目标 1 中，我们将研究血清锌是否充足。 通过进行横断面研究，改变暴露于环境金属的个体的免疫失调 分析存档的群体样本，以了解免疫功能标记物与金属和 血液和尿液样本中的锌水平将测试免疫毒性作用和潜在的影响。 环境项目定义的 U、As 和与环境相关的金属混合物的机制，以及 Aim 3 将在细胞和小鼠模型中测试补充锌是否会降低免疫毒性作用。 膳食补锌是否会减少暴露者免疫失调的生物标志物 这项工作通过将接触暴露结合起来，具有创新性。 通过实验模型中的机制研究来获取暴露人群的信息和生物监测数据。 迄今为止，还没有重大的、基于社区的健康研究描述暴露和免疫学 我们提出了一个新的假设：金属。 暴露会破坏多种对免疫功能至关重要的锌结合蛋白，从而导致免疫 这项研究代表了第一个人类研究。 基于补锌的干预措施可改善混合金属暴露的不利影响。 为了实现研究目标，BP1 与环境项目很好地结合起来，为不同的金属提供信息 暴露、BP2 共享机械数据和模型系统、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将产生显着的结果。 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措施的可行性 减轻金属暴露的不利影响。