Neurovascular Consequences of Inhaled Uranium Mine-Site Dust Exposure

吸入铀矿场粉尘暴露对神经血管的影响

• 批准号: 10094731
• 负责人: Katherine Zychowski
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10094731
• 关键词: Acute; Advisory Committees; Airborne Particulate Matter; Arizona; Arsenic; Arterial Fatty Streak; Automobile Driving; Behavior; Behavioral; Biomedical Research; Blood - brain barrier anatomy; Blood Circulation; Blood Vessels; Cardiovascular Diseases; Carotid Arteries; Carotid Artery Plaques; Communication Research; Communities; Data; Development; Dust; Endothelial Cells; Endothelium; Environmental Exposure; Environmental Health; Environmental Pollution; Exposure to; Extravasation; Functional disorder; Future; Gases; Generations; Goals; Health; Health Sciences; Heavy Metals; Home environment; Impairment; In Vitro; Incidence; Inflammation; Inflammatory; Inflammatory Response; Ingestion; Inhalation; Inhalation Exposure; Intervention; Laboratories; Lead; Link; Lung; Magnetic Resonance Imaging; Mentorship; Metals; Mining; Navajo; Neurologic; New Mexico; Nickel; Outcome; Particulate; Particulate Matter; Pathologic; Pathology; Pathway interactions; Pharmacy (field); Plants; Population; Radial; Recording of previous events; Research; Research Infrastructure; Research Personnel; Research Proposals; Resource Sharing; Rho-associated kinase; Role; Series; Serum; Site; Southwestern United States; Stroke; Techniques; Thrombus; Tissues; Transient Ischemic Attack; Transition Elements; Universities; Uranium; Vanadium; Vascular Diseases; Work; air quality regulation; arm; base; brain parenchyma; burden of illness; career; cerebrovascular; drinking water; endothelial dysfunction; exposure route; in vivo; morris water maze; mouse model; nervous system disorder; neuroimaging; neuroinflammation; neuropathology; neurovascular; neurovascular unit; particle; plaque lesion; prevent; remediation; response; rho; supportive environment; toxic metal; tribal community; wasting

PROJECT SUMMARY 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 PM has been associated with an increase in serum inflammatory potential and subsequent vascular disease. The PM arising from these uranium mines tends to be high in specific toxic metals including vanadium, uranium, and often nickel and arsenic. 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, I have observed that mine site PM is more acutely toxic to the lungs and systemic vasculature 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 three primary objectives: 1) to further explore neurovascular responses following mine-site derived PM exposure using state-of-the art mobile laboratory AirCARE 1 2) to determine the contribution of the Rho A/Rho kinase pathway on neurovascular dysfunction following mine-site derived PM exposure and 3) to examine the ultimate impact of these outcomes on long-term neuropathology and behavior. This project will serve as a five-year platform for my transition to independence. The University of New Mexico (UNM) offers a supportive environment where investigators can take advantage of several shared resources. I will take full advantage of the outstanding facilities at the University of New Mexico Health Sciences Center, including the Biomedical Research and Integrative Neuroimaging Center (BRaIN), where the MRI, Morris Water Maze and Radial Arm Maze are 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PM已被 与血清炎症潜能增加和随后的血管疾病相关。PM崛起 从这些铀矿中提取的铀往往富含特定的有毒金属，包括钒、铀， 镍和砷。吸入矿区产生的PM后对全身健康的全面影响是 未知，但这种对神经血管系统的炎症影响可能会促进神经系统疾病， 对这种机制的解释还有待于发现。因此，本研究的主要目的 建议是发展一个更深入的了解机制，因果关系的基础上，矿山现场衍生PM- 诱发神经血管功能障碍。在初步研究中，我观察到，矿山现场PM更严重， 与区域背景PM相比，对肺和全身血管系统有毒。此外，类似的研究 吸入颗粒物和气体的增加表明BBB功能障碍可导致神经炎症结果。 因此，我的具体目标将服务于三个主要目标：1）进一步探索神经血管反应 使用最先进的移动的实验室AirCARE 1和2），在矿场产生的PM暴露之后， Rho A/Rho激酶通路在矿源性PM后神经血管功能障碍中的作用 暴露和3）检查这些结果对长期神经病理学和行为的最终影响。 这个项目将作为我向独立过渡的五年平台。新墨西哥州 (UNM)提供了一个有利的环境，使调查人员可以利用几个共享资源。我 将充分利用新墨西哥州大学健康科学中心的优秀设施， 包括生物医学研究和综合神经成像中心（BRaIN），在那里， 安置水迷宫和桡臂迷宫。这些研究的数据最终将导致 与靠近废弃铀矿的西南部人口有关的信息，以及 参与空气质量监管的管理机构。