Particulate Matter Radicals as a Trigger of Cerebrovascular Homeostasis

颗粒物自由基作为脑血管稳态的触发因素

• 批准号: 8922003
• 负责人: Slawo M Lomnicki
• 金额: $ 22.2万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-05 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8922003
• 关键词: Air; Alzheimer' s Disease; Amyloid deposition; Animals; Anxiety; Area; Behavior; Behavioral; Biochemical; Biological; Biomedical Research; Blood; Blood - brain barrier anatomy; Blood Circulation; Brain; Brain Injuries; Cell Line; Central Nervous System Diseases; Cerebrovascular system; Chemicals; Child; Chronic; Clinical; Cognition; Cognitive; Complex; Data; Dependence; Deposition; Development; Disease; Dose; Endothelial Cells; Endothelium; Environmental Risk Factor; Epidemiology; Evaluation; Exposure to; Foundations; Free Radicals; Fright; Functional disorder; Future; Generations; Harvest; Health; Heart; Homeostasis; Human; Hydroxyl Radical; In Vitro; Individual; Inflammation; Inflammatory; Learning; Life; Lung; Measures; Membrane; Metals; Methods; Modeling; Monitor; Motor; Mus; Neuraxis; Neurodegenerative Disorders; Neurologic Dysfunctions; Olfactory Nerve; Output; Oxidation-Reduction; Oxidative Stress; Parkinson Disease; Particulate; Particulate Matter; Pathway interactions; Phospholipids; Phosphorylation; Physiological; Play; Population; Process; Proteins; Research; Role; Sampling; Senile Plaques; Silicon Dioxide; Solutions; Surface; System; Tight Junctions; Time; Tissues; Ultrafine; Variant; Vascular Endothelial Growth Factor Receptor; Work; base; behavior measurement; behavioral impairment; cerebrovascular; in vivo; innovation; oxidation; particle; pollutant; programs; research study; social communication; theories; trend

DESCRIPTION (provided by applicant): There is growing evidence that exposure to the elevated levels of ambient air particular matter (PM) may play a role on the onset of many neurodegenerative diseases. Epidemiological data have shown a decrease in cognitive and learning capabilities for children in areas with high concentration of PM in the air. Data also indicate correlation between high air concentration of PM and amyloid � deposition and senile plaque formation. Ultrafine and sometimes fine PM is proven to be transported to the brain either through olfactory nerve path or through systemic circulation; direct evidence and underlying biological mechanism of PM effects on central nervous system diseases remain elusive. Recently, it was discovered that particulate matter contains environmentally persistent free radicals (EPFR), stabilized on the particles and reactive towards hydroxyl radical formation. The proposed project is working under the hypothesis that upon translocation of PM to brain, EPFRs present on the ambient air PM generate hydroxyl radicals in a cyclic redox process. OH radicals induce oxidative stress, damage blood-brain barrier and result in a chronic inflammation condition. One of the biggest challenges to study the ambient air PM in biomedical research is the large variation in the sample composition. Ambient air PM samples are very complex and composed of many chemical compounds and many metals. In addition, samples collected on different days vary significantly in their composition. As a result it is very difficult to establih a correlation between specific component and the observed biological effects. In this exploratory research we are going to develop a model particle that would contain a specific component (EPFR) in a controlled way. We will compare the effects invoked by the model particles with collected ambient air PM based on varying EPFR concentration. This exploratory project will be completed through the following aims: (i) establishing a model of particles with different EPFR speciation and comparing them with ambient air PM. We will evaluate generation of hydroxyl radicals by both synthetic PM and ambient air PM (ii) Analysis of the biological effects of EPFRs (model and ambient air) on the cerebrovascular endothelium in in vitro experiments; (iii) Observation of the EPFR effects on cerebrovascular system and behavioral dysfunction in in vivo experiments. This exploratory proposal is intended to provide extensive preliminary data for the future R01 submission on the effect of the presence of EPFR in the ambient particulate matter on the integrity of the blood-brain barrier and development of neurodegenerative diseases.

描述（由申请人提供）：越来越多的证据表明，接触环境空气中颗粒物 (PM) 水平升高可能会导致许多神经退行性疾病的发生，流行病学数据显示儿童的认知和学习能力下降。数据还表明，空气中高浓度的 PM 和淀粉样蛋白沉积与老年斑形成之间存在相关性，超细颗粒物（有时是细颗粒物）被证明可以通过嗅觉神经输送到大脑。 PM 对中枢神经系统疾病影响的直接证据和潜在生物学机制仍然难以捉摸。最近，人们发现颗粒物中含有环境持久性自由基 (EPFR)，其稳定在颗粒上并对羟基自由基的形成具有反应性。该项目的假设是，PM 转移到大脑后，环境空气 PM 中存在的 EPFR 在循环氧化还原过程中产生羟基自由基，从而诱发氧化应激，损害血脑屏障并导致炎症。导致慢性炎症的生物医学研究中的最大挑战之一是环境空气 PM 样品的成分非常复杂，并且由许多化合物和金属组成。不同日期收集的样品的成分差异很大，因此很难建立特定成分与观察到的生物效应之间的相关性，在这项探索性研究中，我们将开发一种包含特定成分的模型颗粒（ EPFR）在受控的我们将根据不同的 EPFR 浓度，比较模型颗粒与收集的环境空气 PM 所产生的影响。该探索性项目将通过以下目标完成：（i 建立）具有不同 EPFR 形态的颗粒模型，并将其与不同的 EPFR 形态进行比较。我们将评估合成 PM 和环境空气 PM 产生的羟基自由基 (ii) 体外实验中 EPFR（模型和环境空气）对脑血管内皮的生物效应分析；在体内实验中观察 EPFR 对脑血管系统和行为功能障碍的影响，该探索性提案旨在为未来 R01 提交的关于环境颗粒物中 EPFR 的存在对血液完整性的影响提供广泛的初步数据。 -脑屏障和神经退行性疾病的发展。