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

项目摘要和摘要 从20世纪40年代到80年代，公司铀(U)矿在美国西南部建立， 许多人生活在美洲原住民的土地上。由于填海不当和整治不力，周边居民区 家庭受到残留混合金属的影响，包括砷(As)、钒(V)、铀(U)和 镍(Ni)通过摄入和吸入。吸入金属基衍生颗粒物(PM)已被 与循环血清炎症潜势和随后的血管和 神经血管疾病。吸入矿场产生的PM对全身健康的全面影响 尚未阐明的是循环因素，如细胞外小泡(SEV)在驾驶中的作用 炎症性影响还没有得到充分的研究。 在初步研究中，我们观察到矿场PM对肺和肺的毒性更大 血管系统而不是地区性“背景”PM此外，对可吸入颗粒物和 气体表现为内皮功能障碍，可导致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)机械评估PM暴露后SEV的内吞作用和3) 评估矿尘暴露类型(铀矿与非铀矿)与SEV血管之间的关系 已建立的前矿工人类队列中的生物标志物(MIDUS队列，美国的矿业粉尘 州)。这项提议是一项为期五年的创新研究项目，旨在了解 在PM暴露后驾驶毒性反应的SEV。我们将利用尚未完成的设施和 新墨西哥大学健康科学中心的资源，包括自噬、炎症 和代谢(AIM)中心(P20GM121176)，新墨西哥大学金属生物学和金属研究中心 医学(P20GM130422)，UNM流动流行病学实验室(MEL)和我们的长期 与社区伙伴合作，包括矿工科尔法克斯医疗中心流动外展。 由于对电池、计算机芯片和电子产品的需求增加，全球金属矿石开采激增。 能源、环境混合金属暴露已成为职业和环境中令人担忧的问题 环境背景。这些研究的数据最终将导致与金属有关的基本信息- 受影响人群以及参与空气质量监管的管理机构。

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.