Neurotoxicity of Airborne Particles: Role of Chronic Cerebral Hypoperfusion

空气中颗粒的神经毒性：慢性脑灌注不足的作用

基本信息

批准号：
9181323
负责人：
William J Mack
金额：
$ 47.21万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-01-15 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9181323
关键词：
Address Aerosols Affect Air Air Pollution Alpha Particles Applications Grants Area Atherosclerosis Automobile Exhaust Behavioral Bilateral Biological Markers Biology Biometry Blood - brain barrier anatomy Blood Vessels Brain Canis familiaris Carotid Stenosis Cells Cerebral Ischemia Cerebrovascular Disorders Child Chronic Clinical Cognitive Cognitive deficits Collection Complex Corpus Callosum Dementia Environmental Health Environmental Pollutants Epidemiology Exhibits Experimental Models Exposure to Functional disorder Generations Goals Health Hour Individual Inflammation Inflammatory Injury Investigation Joints Knowledge Los Angeles Magnetic Resonance Imaging Mexico Modeling Mus Neurocognition Neurocognitive Neurocognitive Deficit Outcome Measure Oxidative Stress Particulate Matter Pathogenesis Pathway interactions Permeability Pharmacotherapy Pollution Population Principal Investigator Process Public Policy Reactive Oxygen Species Regulation Reproducibility Research Research Personnel Risk Assessment Risk stratification Rodent Role Safety Sampling Scheme Secondary to Senior Scientist Techniques Testing Time Toxic effect Up-Regulation Vulnerable Populations White Matter Hyperintensity aerosolized air filter cerebral hypoperfusion cerebrovascular chemokine clinical imaging cognitive performance cytokine design experimental study mouse model multidisciplinary nano nanoparticle nanoparticulate nervous system disorder neuroinflammation neurotoxicity neurovascular neurovascular injury particle planetary Atmosphere population based programs public health relevance synergism white matter white matter injury

项目摘要

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.

描述（由申请人提供）：拟议的研究计划旨在确定颗粒物（PM）暴露对白质损伤和神经认知能力下降的影响，并在潜在的脑血管疾病（慢性脑灌注不足研究）中进一步研究这些关联。 PM 暴露与动脉粥样硬化性心血管疾病之间存在密切关系，临床影像学、流行病学和药物治疗研究已证实脑血管功能障碍在痴呆和认知缺陷的发生和进展中发挥着关键作用。调查表明，长期接触颗粒物与认知能力低下之间存在关系，但人们对脑血管疾病可能影响这些过程的潜在病理生理学或假定机制知之甚少。拟议的研究利用实验性小鼠模型，通过以下具体目标来解决这些知识空白：1）检查 PM 暴露继发的脑白质损伤的时间过程；2）检查 PM 暴露和慢性脑灌注不足的影响。 (CCH) 对白质损伤和神经认知的影响，3) 为了检查 PM 暴露和 CCH 对炎症、氧化应激和血脑屏障 (BBB) 渗透性的影响，将使用附近的颗粒采样器收集城市 PM。洛杉矶 CA -110 高速公路收集到的气溶胶主要来自车辆交通，样本将被蒸馏成纳米粒子（纳米）并重新气雾化以进行管理。首席研究员改进了双侧颈动脉狭窄 CCH 模型，该模型产生可重复的白质损伤和行为缺陷，将评估 PM 暴露和 CCH 对白质损伤和神经认知能力下降的独立和综合影响。研究人员预计，这些暴露会表现出协同作用，包括炎症、氧化应激和血脑屏障破坏，他们已经组建了一个多学科团队，其中包括具有互补专业知识的资深科学家。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预计将极大地促进对环境污染物神经血管毒性的理解。结果最终会影响公共政策和监管。评估弱势群体的认知健康，并为个人风险评估和分层提供关键的第一步。