Particulate Matter Radicals as a Trigger of Cerebrovascular Homeostasis

描述(由申请人提供)：越来越多的证据表明，暴露在环境空气中特定物质(PM)水平升高可能在许多神经退行性疾病的发病中发挥作用。流行病学数据显示，空气中PM浓度较高的地区儿童的认知和学习能力有所下降。数据还表明，高浓度PM和淀粉样蛋白�沉积与老年斑块形成之间存在相关性。超细，有时甚至精细的PM被证实通过嗅神经通路或通过全身循环运输到大脑；PM在中枢神经系统疾病中作用的直接证据和潜在的生物学机制仍不清楚。最近，人们发现颗粒物中含有环境持久性自由基(EPFR)，这些自由基稳定在颗粒上，并对羟基自由基的形成起反应。拟议的项目是在这样的假设下进行的，即当PM转移到大脑时，存在于环境空气PM上的EPFR在循环氧化还原过程中产生羟基自由基。··自由基导致氧化应激，破坏血脑屏障，导致慢性炎症。在生物医学研究中，研究环境空气PM的最大挑战之一是样品成分的巨大变化。环境空气PM样品非常复杂，由许多化合物和许多金属组成。此外，不同日期采集的样本成分也有很大差异。因此，很难在特定成分和观察到的生物效应之间建立联系。在这项探索性研究中，我们将开发一种模型粒子，它将以受控的方式包含特定的成分(EPFR)。我们将根据不同的EPFR浓度，将模型颗粒物引起的影响与收集的环境空气PM进行比较。这一探索性项目将通过以下目标完成：(I)建立不同EPFR形态的颗粒物模型，并将其与环境空气PM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)体外实验分析EPFR(模型和环境空气)对脑血管内皮细胞的生物学效应；(Iii)体内实验观察EPFR对脑血管系统和行为功能障碍的影响。这一探索性建议旨在为未来R01提交的关于环境颗粒物中EPFR的存在对血脑屏障完整性和神经退行性疾病发展的影响提供广泛的初步数据。

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.