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SPHERE Report Summary

Project ID: 282413
Funded under: FP7-IDEAS-ERC
Country: Italy

Final Report Summary - SPHERE (SPHERE: Susceptibility to Particle Health Effects, miRNAs and Exosomes)

In spite of more than two decades of mechanistic research, the recent statement of air pollution and Cardio Vascular Diseases (CVD) from the American Heart Association remarked that at front of high degree of consistency of the epidemiology findings showing increased air pollution related CVD risk, the evidence on intermediate mechanisms remains moderate or weak. Ambient particles have been shown to produce a strong inflammatory reaction, however inflammatory and oxidative responses have little specificity and can be activated by a multitude of triggers, thus limiting our capability to correlate them to air pollution exposure. Beside proinflammatory mediators, cell-derived membrane vesicles (microvesicles/exosomes, MV/EX) are also released, representing another mode of intercellular communication that has recently become the subject of increasing interest. MV/EX might be the ideal candidate to mediate the effects of air pollution, since potentially they could be produced by the respiratory system, reach the systemic circulation and lead to the development of endothelial dysfunction.
The project SPHERE (Susceptibility to Particle Health Effects, miRNAs and Exosomes) granted by the European Research Council and hosted by the “Università degli Studi”, Milan, Italy, is aimed at investigating whether exposure to air particles and PM-associated metals can modify MV/EX (as quantity, size, membrane molecules, procoagulant activity and miRNAs content) in plasma of human subjects and to investigate whether these alterations may be linked to CVD risk factors and outcomes. The study population includes 2000 overweighed/obese subjects presenting at the Center for Obesity and Weight Control (Fondazione IRCCS Ca’Granda – Ospedale Maggiore Policlinico) in the period 2011-2014. Obese subjects have been shown to be particularly susceptible to the effects of air pollution. Exposure to air pollutants is being assessed using multiple tools: a) use of daily PM10 concentration series from air quality monitors; b) use of daily PM10 concentration estimates by the FARM model (the flexible air quality regional model), a three-dimensional Eulerian grid model for dispersion, transformation and deposition of particulates, capable to simulate PM10 concentration using a 4 km–dispersion grid; c) Metals determination in urine and hair; d) Personal passive samplers (to measure PM), on a subgroup of subjects (n=100).
For each study participants, we investigated the number and the size of MV/EX and the cellular origin of MVs. To identify altered MV/EX -associated miRNAs , we followed a two-stage, split sample study design. The first (discovery) stage involves genome-wide miRNA expression profiling among 1000 of the aforementioned 2000 participants using the OpenArray technology. The second (replication) stage involves a replication analysis of the top 40 miRNAs that resulted from the first stage.
Our study strongly supports the hypothesis that EVs have an important role in mediating cardiovascular effects of PM exposure, possibly through their miRNA cargo, providing a powerful tool of intercellular communication.

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