Neurotoxicity of Airborne Particles: Role of Chronic Cerebral Hypoperfusion

 描述(由申请人提供)：拟议的研究计划旨在确定颗粒物(PM)暴露对脑白质损伤和神经认知功能下降的影响。在潜在脑血管疾病(慢性脑低灌注)的背景下，进一步研究了这些相关性。研究表明，PM暴露与动脉粥样硬化性心血管疾病之间存在很强的相关性。临床影像、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障碍的发生和发展中起着关键作用。研究表明，长期接触PM与认知能力低下之间存在联系，然而，对潜在的病理生理学或可能的机制知之甚少。脑血管疾病可能会影响这些过程。检测空气污染对脑血管疾病的影响的实验研究还很缺乏。这项拟议的研究利用一个实验性的小鼠模型，通过以下具体目的来解决这些知识差距：1)检查PM暴露引起的继发性脑白质损伤的时间过程。2)研究PM暴露和慢性脑低灌注(CCH)对白质损伤和神经认知的影响；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。洛杉矶CA-110高速公路附近的颗粒物采样器将收集城市PM。收集到的气溶胶是新鲜颗粒物的混合物，主要来自车辆交通。样品将被蒸馏成纳米颗粒(Nano)，并重新雾化，通过曝光室给小鼠服用。首席调查员改进了双侧颈动脉狭窄CCH模型，该模型可产生可复制的脑白质损伤和行为缺陷。析因设计将评估PM暴露和CCH对白质损伤和神经认知功能下降的独立和联合影响。当联合使用时，研究人员预计这些暴露将显示出协同作用。损伤的可能机制，包括炎症、氧化应激和血脑屏障的破坏，将被研究。他们组建了一个多学科团队，成员包括在空气污染、神经毒性、血管生物学、神经炎症、血脑屏障病理生理学、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资深科学家。预计从这次R01中获得的新知识将极大地促进对环境污染物神经血管毒性的理解。这些结果最终会影响弱势群体认知健康方面的公共政策和监管，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.