Particulate Matter Radicals as a Trigger of Cerebrovascular Homeostasis

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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.