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.

项目摘要和摘要 从1940年代 - 1980年代开始，在美国西南部建立了铀（U）矿山 许多在美国原住民土地上。由于填海不当和补救措施不良，周围居民 房屋受到残留的混合金属暴露，包括砷（AS），钒（V），铀（U）和 镍（Ni）通过摄入和吸入。吸入金属的特定物质（PM）已经 与循环血清炎症潜力增加以及随后的血管以及 神经血管疾病。继承的矿场衍生PM的全身健康效果的全部范围 尚未阐明和循环因子的作用，例如小细胞外蔬菜（SEV）在驾驶中 炎症影响尚未得到充实。 在初步研究中，我们观察到矿物位置PM对肺部和 血管系统比区域“背景” PM。此外，对遗传组成部分的类似研究和 气体表明内皮功能障碍可驱动血管功能障碍和炎症结果。 因此，我的具体目的将达到三个主要目标1）机械上描述肺sev PM暴露后的生物发生2）机械性评估PM暴露后的SEV内吞作用，3） 评估采矿类型暴露（U开采与非U采矿）与SEV血管之间的关联 在一个既定的前矿工队列（中间队列，联合采矿尘埃）中的生物标志物 国家）。该建议是一个创新的五年研究项目，以了解 PM暴露后驱动有毒反应的SEV。我们将利用未偿还的设施和 新墨西哥大学 - 健康科学中心的资源，包括自噬，炎症 和新陈代谢中心（P20GM121176），新墨西哥大学生物学金属中心和 医学（P20GM130422），UNM移动流行病学实验室（MEL）和我们的长期存在 与社区合作伙伴的合作，包括矿工Colfax医疗中心移动外展。 由于对电池，计算机芯片的需求增加，金属矿石的全球提取飙升 能源，环境混合金属暴露已成为占领和 环境环境。这些研究的数据最终将导致与金属有关的基本信息 暴露的人口以及参与空气质量法规的管理机构。