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

吸入暴露后循环细胞外囊泡的系统影响和新机制

• 批准号: 10733648
• 负责人: Katherine Zychowski
• 金额: $ 51.73万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-20 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733648
• 关键词: Acute; Air Pollution; Airborne Particulate Matter; Arizona; Arsenic; Automobile Driving; Autophagocytosis; Biogenesis; Biological; Biological Assay; Biological Markers; Biology; Blood - brain barrier anatomy; Blood Vessels; California; Chronic; Clinical; Collaborations; Communities; Complement; Data; Disease; Dust; Endocytosis; Endothelium; Environmental Exposure; Epidemiology; Exhibits; Exposure to; Flow Cytometry; Functional disorder; Gases; Health; Health Sciences; Home; Homeostasis; Human; In Vitro; Inflammation; Inflammatory; Ingestion; Inhalation; Inhalation Exposure; Laboratories; Link; Lipids; Lung; Medical center; Medicine; Metabolism; Metal exposure; Metals; Methodology; Mining; Molecular; Molecular Profiling; Native Americans; New Mexico; Nickel; Occupational; Outcome; Particulate; Particulate Matter; Pathologic; Pathology; Pathway interactions; Physiological Processes; Population; Pulmonary Pathology; Recording of previous events; Research; Research Project Grants; Residual state; Resources; Role; Science; Seasons; Serum; Site; Source; Southwestern United States; Suspensions; Testing; Toxic effect; Toxicology; Triglycerides; United States; Universities; Uranium; Vanadium; Vascular Diseases; Vascular System; Water; Work; air quality regulation; climate change; clinical translation; cohort; cytokine; dust storms; endothelial dysfunction; exposed human population; extracellular vesicles; fine particles; in vivo; innovation; intercellular communication; lung basal segment; meter; microchip; nervous system disorder; neurovascular; novel; outreach; remediation; response; superfund site; uptake; wasting

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.

项目概要和摘要 从 20 世纪 40 年代到 1980 年代，美国西南部建立了企业铀 (U) 矿， 许多位于美国原住民土地上，由于开垦不当和整治不力，周围的住宅区被破坏。 家庭容易接触残留的混合金属，包括砷 (As)、钒 (V)、铀 (U) 和 通过摄入和吸入金属颗粒物 (PM) 来摄入镍 (Ni)。 与循环血清炎症电位的增加以及随后的血管和 吸入矿场产生的颗粒物后会产生神经血管疾病。 尚待阐明以及循环因子（例如小细胞外囊泡（sEV））在驾驶中的作用 炎症影响尚未得到充分研究。 在初步研究中，我们观察到矿区 PM 对肺部和肺部的毒性更严重。 血管系统比区域“背景”PM 此外，对吸入颗粒物和颗粒物的类似研究。 气体表明内皮功能障碍，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) 从机械角度评估 PM 暴露后的 sEV 内吞作用 3) 评估采矿粉尘暴露类型（U 采矿与非 U 采矿）与 sEV 血管之间的关联 已建立的前矿工人类队列（MiDUS 队列，美国采矿粉尘）中的生物标志物 该提案是一个为期五年的创新研究项目，旨在了解其机制作用。 sEV 驱动 PM 暴露后的毒性反应 我们将利用先进的设施和技术。 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代谢中心 医学 (P20GM130422)、新墨西哥州移动流行病学实验室 (MEL) 和我们长期合作的 与社区合作伙伴合作，包括矿工科尔法克斯医疗中心移动外展。 由于对电池、计算机芯片和电池的需求增加，全球金属矿石开采量激增 能源、环境混合金属暴露已成为职业和社会关注的问题 这些研究的数据最终将产生与金属相关的重要信息。 暴露人群以及参与空气质量监管的管理机构。