Inhaled Mine-Site Derived Metal Particulate Matter Drives Pulmonary and Systemic Immune Dysregulation

吸入矿场产生的金属颗粒物会导致肺部和全身免疫失调

基本信息

批准号：
10707529
负责人：
Alicia M. Bolt
金额：
$ 24.64万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10707529
关键词：
Address Autoantibodies Autoimmune Autoimmune Diseases Autoimmunity Automobile Driving Biological Monitoring Bone Marrow Cells Chronic Chronic lung disease Coculture Techniques Collaborations Communities Data Development Disease Dust Environmental Exposure Epithelial Cells Exhalation Exposure to Geography Goals Health Human Hyperactivity Image Immune Immune System Diseases Immunologic Markers Immunologics In Vitro Individual Inflammation Inflammation Mediators Inflammatory Inflammatory Response Inhalation Inhalation Exposure Interstitial Lung Diseases Iron Link Lung Machine Learning Macrophage Measures Mediating Metal exposure Metals Minerals Mining Modeling Mus Navajo New Mexico Nuclear Outcome Oxidative Stress Particulate Particulate Matter Pathology Pathway interactions Physical condensation Population Pueblo Race Pulmonary Inflammation Research Respiration Disorders Risk Role Route Sampling Silicon Dioxide Silicosis Site Southwestern United States Superfund Toxic effect Translating Universities Uranium Vanadium Work bone cohort community living cytokine exposed human population extracellular imaging platform immunoregulation in vitro Model inflammatory marker inhibitor innovation insight lung development lung injury member metal complex metal poisoning mouse model nasopharyngeal swab neutrophil novel pre-clinical programs research study response systemic autoimmunity tool tribal community tribal lands

项目摘要

Project Summary/Abstract Inhalation of mine site dust is a relevant route of human exposure to metal mixtures that poses a significant health concern for tribal communities living near abandoned uranium and hard rock mine sites in the four- corners region of the Southwestern United States. The University of New Mexico's Metals Exposure and Toxicity Assessment on Tribal Land in the Southwest (UNM METALS) team has demonstrated that exposure of individuals in the Navajo Nation to metal mixtures is associated with biomarkers of immune dysregulation and living in close proximity to abandoned uranium mines correlates with levels of anti-nuclear autoantibodies. This region is also a geographic epicenter for interstitial lung disease, silicosis and other chronic respiratory disorders, which are linked to environmental exposures and systemic autoimmunity. It is currently not known how inhaled metal-rich particulates drive extrapulmonary immunological dysregulation. In addition, the contribution of different individual metals (e.g., uranium, vanadium, and iron) in driving these immune-mediated changes has yet to be clearly defined. BioProject – Lung (BP Lung) focuses on investigating mechanisms of metal-mediated immune dysregulation both locally in the lungs, as well as systemically following inhalation exposure to metal-rich particulates. Thus, our main objective is to determine how these changes contribute to pulmonary injury and autoimmune development. Because metals accumulate in bone and we have evidence that inflammatory changes in the bone marrow niche mirror pulmonary responses following particulate exposure, a second goal is to investigate crosstalk between the bone marrow niche and the lungs contributing to metal particulate-mediated immune dysfunction. Our central hypothesis is that uranium and uranium-rich particulate mixtures drive pulmonary and systemic immune dysregulation and autoimmunity through hyperactive NETosis, in part by priming neutrophils for NETosis in the bone marrow niche. In Aim 1, we will utilize a novel high content imaging, machine learning-based single cell platform to investigate how individual metals alone or in combination with other metals and minerals contribute to oxidative stress, inflammation, and NETosis using human, in vitro models. In Aim 2, we will use an autoimmune prone mouse model to determine the role of neutrophils and NETosis in the development of airborne metal-mediated lung and systemic immune dysregulation and autoimmune development using several established NETosis inhibitors. In Aim 3, we will translate our mechanistic findings from Aims 1 and 2 to investigate associations between airborne metal exposure and airway inflammatory mediators in individuals from Laguna Pueblo partnering community in collaboration with BP Comm and CEC. This work is innovative and significant because it utilizes state-of-the art tools to provide detailed understanding of the effect of neutrophils and NETosis as mechanistic targets and driver of systemic immune dysregulation following metal particulate exposure and how crosstalk between the bone marrow niche and the lungs contribute to these pathologies.

项目概要/摘要吸入矿场粉尘是人类接触金属混合物的一个相关途径，对人体造成重大影响。居住在四个地区废弃铀矿和硬岩矿场附近的部落社区的健康问题美国西南部的角落地区的新墨西哥大学金属暴露和西南部落土地毒性评估 (UNM METALS) 团队证明，接触纳瓦霍族人接触金属混合物的比例与免疫失调的生物标志物有关居住在废弃铀矿附近与抗核自身抗体水平相关。该地区也是间质性肺病、矽肺病和其他慢性呼吸道疾病的地理中心。目前尚不清楚与环境暴露和系统性自身免疫有关的疾病。吸入富含金属的颗粒如何导致肺外免疫失调。不同个体金属（例如铀、钒和铁）在驱动这些免疫介导的过程中的贡献变化尚未明确定义。BioProject – Lung（BP Lung）专注于研究机制。金属介导的肺部局部免疫失调以及吸入后的全身免疫失调因此，我们的主要目标是确定这些变化如何影响。因为金属在骨骼中积聚，我们有证据表明肺损伤和自身免疫发展。骨髓生态位的炎症变化反映了颗粒物后的肺部反应暴露，第二个目标是研究骨髓生态位和肺部之间的串扰我们的中心假设是金属颗粒介导的免疫功能障碍。颗粒混合物通过以下方式驱动肺部和全身免疫失调和自身免疫过度活跃的 NETosis，部分是通过在骨髓生态位中启动中性粒细胞进行 NETosis 在目标 1 中，我们将。利用一种新颖的高内涵成像、基于机器学习的单细胞平台来研究个体如何金属单独或与其他金属和矿物质结合会导致氧化应激、炎症和使用人类体外模型进行 NETosis 在目标 2 中，我们将使用易发生自身免疫的小鼠模型来确定。中性粒细胞和 NETosis 在空气金属介导的肺和全身免疫系统发育中的作用在目标 3 中，我们将使用几种已建立的 NETosis 抑制剂来治疗失调和自身免疫发展。将我们从目标 1 和目标 2 中得到的机械结果转化为调查空气中金属之间的关联拉古纳普韦布洛合作社区个体的暴露和气道炎症介质与 BP Comm 和 CEC 的合作这项工作具有创新性且意义重大，因为它利用了最新技术。艺术工具可提供对中性粒细胞和 NETosis 作为机械目标的影响的详细了解金属颗粒暴露后全身免疫失调的驱动因素以及金属颗粒之间的串扰骨髓生态位和肺部会导致这些病变。