Particulate Matter-Induced Pulmonary Exosomes and the Lung-Brain Axis

颗粒物诱导的肺外泌体和肺脑轴

基本信息

批准号：
10302568
负责人：
Katherine Zychowski
金额：
$ 22.73万
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：
2021
资助国家：
美国
起止时间：
2021-07-16 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10302568
关键词：
Acute Address Aging Air Pollution Airborne Particulate Matter Arsenic Automobile Driving Biological Biomedical Research Birth Blood - brain barrier anatomy Blood Vessels Brain Carbon Black Caveolae Cell Communication Cells Child Clathrin Cohort Studies Data Diet Disease Dust Endocytosis Endothelial Cells Endothelium Environment Environmental Exposure Environmental Wind Exposure to F-Actin Functional disorder Gases General Population Genetic Transcription Health Health Sciences Health Services Health Services Accessibility Heavy Metals Home Homeostasis In Vitro Individual Inflammatory Inhalation Injections Institutes Knowledge Lead Life Link Lung Magnetic Resonance Imaging Mediating Mental disorders Metals Mus Native Americans Navajo Neurologic New Mexico Nickel Ontology Outcome Particulate Particulate Matter Pathologic Peptide Fragments Population RNA Recording of previous events Research Research Personnel Research Proposals Resource Sharing Role Serum Signal Transduction Site Socioeconomic Factors Southwestern United States Stroke Substance abuse problem Tail Testing United States National Institutes of Health Universities Uranium Vanadium Vascular Dementia Vascular Diseases Veins Vesicle air filter air quality regulation base behavioral health blood-brain barrier disruption brain health cellular imaging cerebrovascular endothelial dysfunction exosome fine particles high reward high risk in vivo nervous system disorder neuroimaging neuroinflammation neurovascular remediation response social success tribal community

项目摘要

PROJECT SUMMARY AND ABSTRACT Corporate uranium mines were established in the Southwestern United States from the 1940s-1980s, leaving behind poorly remediated sites near surrounding residential homes. Inhaled, mine-site derived particulate matter (PM) has been associated with an increase in serum inflammatory potential and subsequent vascular and neurological disease. The PM arising from these uranium mines tends to be high in specific toxic, inorganic metals including vanadium (V), uranium (U), and often nickel (Ni) and arsenic (As). The full scope of systemic health effects following inhaled mine-site derived PM is unknown, but such inflammatory impacts to the neurovasculature could promote neurological diseases and the elucidation of such mechanisms has yet to be discerned. Therefore, the primary objective of this research proposal is to develop a deeper understanding of the mechanistic, causal basis for mine-site derived PM-induced neurovascular dysfunction. In preliminary studies, we have observed that mine site PM is more acutely toxic to the lungs and brain compared to regional background PM. Furthermore, similar studies of inhaled particulates and gases demonstrate a BBB dysfunction that can drive neuroinflammatory outcomes. Therefore, my specific aims will serve two primary objectives: 1) mechanistically delineate the contribution of circulating PM-induced exosomes as drivers of cerebrovascular endothelial barrier dysfunction and neuroinflammation. 2) quantitatively assess endothelial cell dynamics following treatment with circulating exosomes from PM-exposed mice using high-content, single-cell imaging. This proposal will serve as a high-risk, high reward project in a supportive academic environment where investigators can take advantage of several shared resources. We will take full advantage of the outstanding facilities at the University of New Mexico Health Sciences Center, including the Brain and Behavioral Health Institute (BBHI) and the Biomedical Research and Integrative Neuroimaging Center (BRaIN), where the MRI, is housed. Data from these studies will ultimately lead to essential information pertinent to Southwestern populations in close proximity to abandoned uranium mines, as well as governing agencies involved in air-quality regulations.

项目概要和摘要 20 世纪 40 年代至 80 年代，美国西南部建立了企业铀矿，导致在周围住宅附近修复不良的场地后面。吸入的、矿场产生的颗粒物 (PM) 与血清炎症潜力的增加以及随后的血管和神经系统疾病。这些铀矿产生的颗粒物往往含有大量特定的有毒、无机物金属包括钒 (V)、铀 (U)，通常还包括镍 (Ni) 和砷 (As)。系统性的全面范围吸入矿场产生的颗粒物对健康的影响尚不清楚，但这种炎症对人体的影响神经血管系统可能促进神经系统疾病，但这种机制尚未阐明。看出了。因此，本研究计划的主要目标是加深对矿区颗粒物引起的神经血管功能障碍的机制和因果基础。在初步研究中，我们观察到，与区域性环境相比，矿区 PM 对肺部和大脑的毒性更严重背景下午。此外，对吸入颗粒物和气体的类似研究表明血脑屏障功能障碍这可能会导致神经炎症结果。因此，我的具体目标将服务于两个主要目标：1）机械地描述循环 PM 诱导的外泌体作为脑血管驱动因素的贡献内皮屏障功能障碍和神经炎症。 2) 定量评估内皮细胞动力学使用高内涵单细胞成像对来自 PM 暴露小鼠的循环外泌体进行治疗后。该提案将在支持性学术环境中作为一个高风险、高回报的项目，其中调查人员可以利用多种共享资源。我们将充分发挥优秀优势新墨西哥大学健康科学中心的设施，包括大脑和行为健康中心研究所 (BBHI) 和生物医学研究和综合神经影像中心 (BRaIN)，其中 MRI 位于安置。这些研究的数据最终将产生与西南航空相关的重要信息废弃铀矿附近的居民以及参与空气质量管理的机构法规。