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

项目摘要和摘要 20世纪40年代至80年代，公司铀矿在美国西南部建立，留下了 在周围民居附近补救不力的地点后面。矿场可吸入颗粒物 (PM)与血清炎症潜能和随后的血管和 神经系统疾病。这些铀矿产生的PM往往含有较高的特定有毒、无机 金属包括钒(V)、铀(U)，通常还有镍(Ni)和砷(As)。全面性系统性 吸入矿场产生的PM对健康的影响尚不清楚，但这种炎性影响对 神经血管系统可促进神经系统疾病，但其机制尚未阐明。 洞察力很强。因此，这项研究提案的主要目的是加深对 矿场PM所致神经血管功能障碍的机制和因果基础。在预赛中 研究发现，矿场PM对肺部和大脑的毒性比地区性的强 后台PM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性后果。因此，我的具体目标将服务于两个主要目标：1) 机制描述循环PM诱导的外切体作为脑血管驱动因素的作用 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 在使用高含量单细胞成像技术对PM暴露小鼠的循环外切体进行治疗后。 这项提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中发挥作用 调查人员可以利用几个共享的资源。我们将充分利用优秀的 新墨西哥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(大脑)，核磁共振是在那里， 有房住。来自这些研究的数据最终将导致与西南大学有关的基本信息 离废弃铀矿很近的人口以及参与空气质量的管理机构 规章制度。

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.