MICRORNAS IN CIRCULATION: ONTOLOGIES OF ASTHMA SEVERITY AND TREATMENT (MICROCOAST)

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 DESCRIPTION (provided by applicant): Asthma affects over 300 million individuals worldwide. MicroRNAs (miRNAs) are small noncoding ribonucleic acids (RNAs) that regulate protein synthesis by way of gene trans-repression or RNA silencing. A growing number of studies demonstrate that miRNAs control signaling pathways in every cell type and regulate inflammation. Thus, miRNAs likely play a profound role in the pathogenesis of asthma. Early miRNA studies have identified several miRNAs associated with asthma and corticosteroid treatment response. The presence of miRNAs stably expressed in blood indicate that miRNAs may be used as noninvasive biomarkers of asthma and asthma treatment response. The major goal of this project is to systematically investigate the role of circulating miRNAs in asthma severity and asthma treatment response. To accomplish this, we have specified three related but independent aims. The first aim evaluates data from the genome-wide sequencing of miRNAs in the serum of 500 asthmatics for their association with asthma severity at the time of enrollment into large clinical trial cohorts. The miRNA markers with the strongest evidence for differential expression will be tested for replication an independent clinical cohort and modeled using co-expression networks. The second aim seeks to understand the genomic basis for drug treatment response (pharmacogenomics). This aim will assess the genome-wide miRNAs for their differential expression with drug treatment response, as defined by change in lung function in response to inhaled corticosteroid medications. These miRNAs will be tested for replication in an independent clinical trial and then modeled using a Bayesian network approach for their ability to predict response to inhaled corticosteroids in asthma. Our final aim will be to interrogate the functional basis for our circulating miRNA findings in cellular models of airway smooth muscle function. Using miRNA mimics, our top miRNAs from our differential expression analyses will be tested for their ability to modulate airway smooth muscle proliferation and contractility (aim 1 miRNAs) or for their ability to mediate corticosteroid signaling (aim 2 miRNAs) in cells obtained from asthmatics. By simultaneously examining changes in gene expression, the mechanistic basis for the physiologic changes can be inferred. We believe that these findings will uncover the role of miRNAs basis for asthma severity and treatment response and lead to novel interventions to predict and alleviate this major health care problem.