Systemic Implications and Novel Mechanisms of Circulating Extracellular Vesicles Following Inhaled Exposures

项目总结和摘要 从20世纪40年代到80年代，美国西南部建立了公司铀矿， 许多在美洲原住民的土地上。由于填海不当、整治不力，周边居民 家庭受到残留的混合金属暴露，包括砷（As），钒（V），铀（U）， 镍（Ni）通过摄入和吸入。吸入的基于金属的衍生颗粒物（PM）已被 与循环血清炎症潜能增加和随后的血管和 神经血管疾病吸入矿区产生的PM后对全身健康的全面影响， 还有待阐明和循环因子的作用，如小细胞外囊泡（sEV）在驱动 炎症的影响还未被充分研究。 在初步研究中，我们观察到矿区PM对肺和呼吸系统的急性毒性更大， 血管系统比区域“背景”PM。此外，对吸入颗粒物和 气体显示内皮功能障碍，其可驱动血管功能障碍和炎症结果。 因此，我的具体目标将服务于三个主要目标：1）机械地描绘肺sEV PM暴露后的生物发生2）机械评价PM暴露后的sEV内吞作用和3） 评估采矿粉尘暴露类型（铀矿开采与非铀矿开采）与sEV血管之间的关联 在一个已建立的前矿工人类队列（MiDUS队列，美国矿业粉尘）中， 国家）。该提案是一项为期五年的创新研究项目，旨在了解 sEV在PM暴露后驱动毒性反应。我们将利用现有的设施， 新墨西哥州大学健康科学中心的资源，包括自噬，炎症 和代谢（AIM）中心（P20 GM 121176），新墨西哥州大学生物学金属中心和 医学（P20 GM 130422），UNM移动的流行病学实验室（MEL）和我们长期以来的 与社区合作伙伴的合作，包括矿工的科尔法克斯医疗中心移动的推广。 随着全球金属矿石开采量的激增，由于对电池，计算机芯片和 能源，环境混合金属暴露已成为一个关注的问题，在职业和 环境背景。这些研究的数据将最终导致与金属相关的基本信息- 暴露人群以及参与空气质量法规的管理机构。

PROJECT SUMMARY AND ABSTRACT From the 1940s-1980s, corporate uranium (U) mines were established in the Southwestern United States, many on Native American lands. Due to improper reclamation and poor remediation, surrounding residential homes are subject to residual mixed-metals exposure including arsenic (As), vanadium (V), uranium (U), and nickel (Ni) via ingestion and inhalation. Inhaled metal-based derived particulate matter (PM) has been associated with an increase in circulating serum inflammatory potential and subsequent vascular and neurovascular disease. The full scope of systemic health effects following inhaled mine-site derived PM has yet to be elucidated and the role of circulating factors, such as small extracellular vesicles (sEVs) in driving inflammatory impacts is underexplored. In preliminary studies, we have observed that mine-site PM is more acutely toxic to pulmonary and vascular systems than regional ‘background’ PM. Furthermore, similar studies of inhaled particulates and gases demonstrate endothelial dysfunction that can drive vascular dysfunction and inflammatory outcomes. Therefore, my specific aims will serve three primary objectives 1) mechanistically delineate lung-sEV biogenesis following PM exposure 2) mechanistically evaluate sEV endocytosis following PM exposures and 3) assess associations between type of mining dust exposure (U-mining vs. non-U mining) and sEV vascular biomarkers in an established human cohort of former miners (the MiDUS cohort, Mining Dust in the United States). This proposal serves as an innovative, five-year research project to understand the mechanistic role of sEVs in driving toxic responses following PM exposure. We shall leverage the outstanding facilities and resources at the University of New Mexico – Health Sciences Center, including the Autophagy, Inflammation and Metabolism (AIM) Center (P20GM121176), the University of New Mexico Center for Metals in Biology and Medicine (P20GM130422), the UNM Mobile Epidemiology Laboratory (MEL) and our long-standing collaborations with community partners, including the Miners’ Colfax Medical Center Mobile Outreach. With global extraction of metal ores surging due to increased demand for batteries, computer chips and energy, environmental mixed-metals exposure has become an issue of concern in both an occupational and environmental context. Data from these studies will ultimately lead to essential information pertinent to metal- exposed populations, as well as governing agencies involved in air-quality regulations.