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

项目总结和摘要 从20世纪40年代到80年代，公司铀矿在美国西南部建立， 在周围居民住宅附近的补救措施不力的地点后面。吸入的、矿场产生的颗粒物 (PM)与血清炎症潜能的增加以及随后的血管和 神经系统疾病从这些铀矿产生的PM往往是高的特定有毒，无机 金属包括钒（V）、铀（U），通常还有镍（Ni）和砷（As）。全面系统性 吸入矿址产生的PM后对健康的影响尚不清楚，但这种对人体的炎症影响 神经血管系统可以促进神经系统疾病，并且这种机制的阐明还有待于进一步研究。 察觉。因此，本研究提案的主要目标是加深对 矿址衍生PM诱发的神经血管功能障碍的机制和因果基础。初步 研究，我们已经观察到，与区域相比，矿区PM对肺部和大脑的急性毒性更大。 后台PM此外，对吸入颗粒和气体的类似研究表明， 会导致神经炎症因此，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疾病的驱动因素的贡献， 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 在用来自PM暴露小鼠的循环外泌体处理后，使用高含量单细胞成像。 这个建议将作为一个高风险，高回报的项目，在一个支持性的学术环境， 调查人员可以利用若干共享资源。我们将充分利用 新墨西哥州大学健康科学中心的设施，包括大脑和行为健康 研究所（BBHI）和生物医学研究和综合神经成像中心（BRaIN），其中MRI，是 安置好了这些研究的数据将最终导致与西南地区相关的重要信息 废弃铀矿附近的居民，以及参与空气质量管理的管理机构 规定

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.