Air pollution is a major public health concern in the US and worldwide. Exposure to air particulate matter (PM)with an aerodynamic diameter <2.5 m (PM2.5) is well known to increase cardiovascular incidence andmortality. Inhaled PM2.5 induces systemic pro-inflammatory response and oxidative-stress, two majorcardiovascular disease (CVD) pathways. Blood leukocyte gene expression profiling in highly PM-exposedsubjects has revealed that systemic inflammatory responses are initiated through extensive gene expressionshifts but mechanisms regulating the gene expression changes are largely unexplored. MicroRNAs (miRNAs)are small RNA molecules that have newly emerged as key regulators of gene expression. Inflammation andoxidative stress have been shown to alter miRNA expression, which can be controlled by their encoding geneDNA methylation status. Our preliminary data have shown that PM2.5 exposure changed the expression levelsof certain miRNAs in blood leukocytes in a highly PM-exposed population. We hypothesize that PM exposure-induced oxidative stress and inflammatory response may cause blood leukocyte miRNA expression changesthat regulate gene expression profiles. Gene expression alterations may then cause certain changes incirculating biomarkers and cardiovascular physiology to favor CVD development.We propose to test these hypotheses using data from the Beijing Truck Driver Air Pollution Study (BTDAS), ourrecently completed study in Beijing, China, one of the most polluted cities in the world. Thanks to specialfunding by the Italian Ministry of Scientific Research, the BTDAS was conducted shortly before the Beijing2008 Olympic Games (June 15 to July 27, 2008). Two groups of subjects were recruited, i.e., 60 truck drivers(high exposure) and 60 indoor workers (low exposure). We collected personal PM2.5 and its toxic metalexposure data via air monitors and continuous EKG data via Holter monitors during their work hours, and bloodsamples at the end of work, on two independent work days with 1-2 week intervals. We propose to conduct anancillary study to 1) identify PM2.5- and its toxic metal-related miRNA expression signatures by performing anunbiased screening of miRNAs using highly quantitative Next Generation Sequencing; 2) examine whethermiRNA expression is associated with encoding gene methylation status; 3) determine whether PM-relatedmiRNA signatures are associated with CVD measures using our already measured data on plasmainflammatory and blood clotting markers, blood pressure and EKG. Given the general public's ubiquitousexposure to air pollution, this research is of high significance. This study is designed to take full advantage ofthe unique specimen repository as well as previously collected data and examined measures to potentiallyidentify novel mechanisms linking air pollution with CVD, and thus provide the potential to identify importantCVD preventive strategies.
Lay summary Air pollution is a well known contributor to cardiovascular disease (CVD) and death but the underlying mechanisms remain poorly understood. Traffic is a major source of air pollution and due to the general public's unavoidable exposure;this research has important and far-reaching public health implications. This study is designed to identify novel mechanisms related to miRNAs, small molecules that are newly discovered to control gene expression, linking air pollution with CVD. Analysis of data from a highly air pollution-exposed population in Beijing, China, will have the potential to identify mechanisms that may not be detectable in a low exposed population, thus providing the groundwork to develop important novel preventive strategies for future potential CVD intervention efforts.
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