Asthma is a chronic inflammatory disease of the airways characterized by bronchial hyperreactivity and airway inflammation that increasingly afflicts the United States population. Individuals with severe asthma, suffer the most and drive at least 50% of the healthcare costs due to asthma in the U.S. To improve our understanding of this and other subgroups of this disease, the NHLBI initiated the Severe Asthma Research Program (SARP). This program identified 5 subgroups of asthma with different phenotypic features, of these, cluster 5 is characterized by severe irreversible airflow obstruction indicatin that airway remodeling is a key feature that discriminates the most severe subgroups of disease. Many of the molecular mechanisms that underlie airway remodeling have not been clearly elucidated in individuals with asthma. One of the main barriers to the characterization of airway remodeling has been the lack of safe access to the airway tissue itself in individuals with severe airflow impairment. In an effort to define novel pathways associated with the pathobiology of airway remodeling in asthma, our research team at the Yale Center for Asthma and Airways Disease (YCAAD) has developed a non-invasive protocol to measure genome-wide gene expression in the sputum of individuals with asthma. To identify regulatory genes that are associated with the development of airway remodeling and its relation with SARP clusters, we determined the effect of expression of microRNAs (miRNAs) on airflow obstruction in the YCAAD dataset. Analysis of miRNA expression in cells isolated from induced sputum with the Affymetrix 1.0 ST microarray identified an inverse correlation between hsa-miR-504 and baseline forced expiratory volume in 1 second (FEV1). In addition, hsa-miR-504 correlated positively with sputum levels of YKL-40, a chitinase-like protein we have previously shown to be associated with airway remodeling and increased asthma severity. A computational analysis overlapping the predicted hsa-miR-504 targets with the sputum gene expression profile, identified 90 transcripts that are likely to be hsa-miR-504 targets when a False Discovery Rate (FDR <0.05) threshold is used. Based on these exciting findings, we hypothesize that changes in the expression of hsa-miR-504 are indicative of asthma severity and that these changes lead to distinct changes in the expression of genes important in persistent inflammation and airway remodeling. To address this hypothesis we will focus on the following specific aims: 1). Determine the relationship between sputum hsa-miR-504, asthma and asthma severity. 2). Determine the cellular sources, immunophenotype and biologic targets of hsa-miR-504 in the sputum of individuals with asthma. 3). Identify a severe asthma phenotype associated with hsa-miR-504 and monitor its impact on adverse outcomes and changes in lung function through the longitudinal evaluation of subjects with asthma.
Our research efforts will center on the impact of the microRNA 504 in asthma, in particular, severe disease. Severe asthma accounts for nearly $28 Billion dollars in healthcare expenses yearly. The ultimate goal is to identify novel therapies for severe asthma, targeting this specific microRNA and the genes it regulates.
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