miR-135a and miR-204 in Pulmonary Hypertension induced by antigen and urban air pollution

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 DESCRIPTION (provided by applicant): miR-135a and miR-204 in Pulmonary Hypertension induced by antigen and urban air pollution Abstract Strong environmental influences have been critical in the lung and heart disease. Specially, inhalation of urban particulate matter (PM) has been associated with a host of cardiovascular and respiratory diseases. Pulmonary hypertension (PH) shows the increase of blood pressure in the pulmonary arteries due to remodeling and constriction of the pulmonary arteries. Previous studies in our lab indicate that severe pulmonary arterial remodeling can be caused by T helper 2 (Th2) immune response. Since then we found that this response is exacerbated by urban particulate matter from air pollution. In this case, both pulmonary arterial remodeling and increased right heart pressure are induced. Further our studies showed that IL-13 and IL-17A are involved in developing pulmonary hypertension induced by antigen and PM. The expending studies have shown a variety of cause in the complex mechanism of pathogenesis of pulmonary hypertension, but the molecular mechanisms of pathogenesis of pulmonary hypertension are still insufficiently understood. In this project, the applicant proposes to understand the epigenetic mechanisms that cause the pulmonary hypertension phenotype induced by exposure to combined antigen (Ovalbumin, OVA) and urban particulate matter (PM) in mice. To identify the epigenetic mechanism, we focus on miR-135a and miR-204 in this proposal because of our preliminary studies. Our preliminary data showed that miR-135a was up-regulated in the lungs of mice exposed to OVA-PM and that this was significantly controlled by combination of IL-13 and IL-17A. Further miR-204 was down-regulated in the lungs of mice exposed to OVA-PM and that this was also significantly controlled by combination of IL-13 and IL-17A. Based on these data, the applicant proposes to test two working hypotheses: The first hypothesis is that up-regulation of miR-135a is a critical regulator of the pulmonary hypertension phenotype in mice exposed to OVA and PM. The second hypothesis is that down-regulation of miR-204 is a critical regulator of the pulmonary hypertension phenotype in mice exposed to OVA and PM. The long-range goals of this project are to understand if miR-135a or miR-204 would be a biomarker to track pollution exposure induced exacerbations of chronic lung diseases such as pulmonary hypertension, or if blocking miR-135a or injection of miR-204 would be a new therapeutic modality for exacerbations of chronic lung disease caused by exposure to urban air pollution.