Neurotoxicity of Airborne Particles: Role of Chronic Cerebral Hypoperfusion

 描述（由申请方提供）：拟定的研究计划旨在确定颗粒物（PM）暴露对白色物质损伤和神经认知功能下降的影响。在潜在脑血管疾病（慢性脑灌注不足）的背景下进一步检查这些相关性。研究已经建立了PM暴露和动脉粥样硬化性心血管疾病之间的密切关系。临床影像学、流行病学和药物治疗研究已经证实脑血管功能障碍在痴呆和认知缺陷的发生和发展中起着关键作用。研究表明，长期PM暴露和低认知能力之间的关系，但是，很少有人知道潜在的病理生理学或推定的机制。脑血管疾病可能会影响这些过程。目前还缺乏有关空气污染对脑血管疾病影响的实验研究。拟议的调查利用实验鼠模型，以解决这些知识差距，通过以下具体目标：1）检查的时间过程中的白色物质损伤继发于PM暴露。2)研究PM暴露和慢性脑灌注不足（CCH）对白色物质损伤和神经认知功能的影响; 3）研究PM暴露和CCH对炎症、氧化应激和血脑屏障（BBB）通透性的影响。城市PM将在洛杉矶CA-110高速公路附近用颗粒采样器收集。收集的气溶胶代表新鲜PM的混合物，主要来自车辆交通。将样品蒸馏成纳米颗粒（纳米）并重新雾化，通过暴露室给予小鼠。主要研究者改进了双侧颈动脉狭窄CCH模型，该模型可产生可重现的白色物质损伤和行为缺陷。析因设计将评估PM暴露和CCH对白色物质损伤和神经认知下降的独立和联合作用。当一起给药时，研究者期望这些暴露表现出协同作用。损伤的推定机制，包括炎症，氧化应激和血脑屏障破坏，将进行检查。他们组建了一个多学科团队，包括在空气污染神经毒性，血管生物学，神经炎症，BBB病理生理学，神经认知，环境健康科学流行病学和生物统计学方面具有互补专业知识的高级科学家。预期从R 01获得的新知识将大大促进对环境污染物神经血管毒性的理解。研究结果最终会影响弱势人群认知健康方面的公共政策和法规，并为个人风险评估和分层提供关键的第一步。

 DESCRIPTION (provided by applicant): The proposed research program seeks to determine the impact of particulate matter (PM) exposure on white matter injury and neurocognitive decline. These associations are further examined in the setting of underlying cerebrovascular disease (chronic cerebral hypoperfusion). Studies have established a strong relationship between PM exposure and atherosclerotic cardiovascular disease. Clinical imaging, epidemiology and pharmacotherapy studies have verified a critical role for cerebral vascular dysfunction in the onset and progression of dementia and cognitive deficits. Investigations suggest a relationship between long-term PM exposure and low cognitive performance, however, little is known about underlying pathophysiology or putative mechanisms. Cerebrovascular disease may affect these processes. Experimental studies examining effects of air pollution in the setting of cerebrovascular disease are lacking. The proposed investigation utilizes an experimental murine model to address these knowledge gaps through the following specific aims: 1) To examine the time course of white matter injury secondary to PM exposure. 2) To examine the effects of PM exposure and chronic cerebral hypoperfusion (CCH) on white matter injury and neurocognition and, 3) To examine the impact of PM exposure and CCH on inflammation, oxidative stress and blood-brain-barrier (BBB) permeability. Urban PM will be collected with a particle sampler near the CA-110 Freeway in Los Angeles. Collected aerosols represent a mix of fresh PM, predominantly from vehicular traffic. Samples will be distilled to nanoparticles (nano) and re-aerosolized for administration to mice through exposure chambers. The Principal Investigator has refined a Bilateral Carotid Stenosis CCH model which generates reproducible white matter injury and behavioral deficits. A factorial design will assess independent and combined effects of PM exposure and CCH on white matter injury and neurocognitive decline. When administered together, the investigators expect these exposures to exhibit synergy. Putative mechanisms of injury including inflammation, oxidative stress and BBB breakdown, will be examined. They have assembled a multidisciplinary team including senior scientists with complementary expertise in air pollution neurotoxicity, vascular biology, neuroinflammation, BBB pathophysiology, neurocognition, environmental health science epidemiology and biostatistics. Expected new knowledge gained from this R01 will greatly advance the understanding of neurovascular toxicity of environmental pollutants. Results can ultimately impact public policies and regulation with respect to cognitive health in a vulnerable population and provide a critical first step towards individual risk assessment and stratification.