Poorly controlled asthma in children results in repeat exacerbations and hospitalization. The response to standard treatment for asthma exacerbation is heterogeneous among hospitalized children and a significant subset of patients responds poorly to therapy. Our long-term goal is to understand the molecular mechanisms for diverse treatment responses and identify reliable associated biomarkers. The objective of this R21 application, which is a step towards attainment of our long-term goal, is to establish the feasibility of identifying characteristic methylation signatures associated with distinct treatment response groups among children hospitalized with asthma exacerbation. Our central hypothesis is 1) DNA methylation profiles in asthmatic children are subject to alteration by standard asthma exacerbation treatment, resulting in gene dysregulation;and 2) these methylation profiles are associated with distinct clinical responses to treatment among asthmatic children. To test our hypothesis, we propose to assay DNA methylation status at more than 4.6 million CpG sites across the genome in nasal epithelial cells from children hospitalized with asthma exacerbation, and determine their correlation with gene expression levels and patients'clinical phenotypes. Expected outcomes of the proposed studies include 1) the identification of genes with DNA methylation changes as potential contributing factors to asthma development and exacerbation;and 2) the identification of DNA methylation markers correlated with distinct clinical treatment response, laying the ground for future studies designed to predict treatment response in children hospitalized with asthma exacerbation using genomic and epigenomic profiles. The research proposed in this exploratory R21 is significant because it would have a positive impact by enabling the development of more personalized treatment options for asthma exacerbation. The characteristic DNA methylation signatures associated with poor response to therapy can be used for identifying hospitalized asthmatic children who may need alternative or additional treatment strategies. Furthermore, it will identify critical genes and pathways in these "poor responders" that may be the most optimal targets for intervention for this subcategory of patients.
The proposed studies are relevant to public health because they seek to identify DNA methylation biomarkers associated with standard treatment of asthma exacerbation and clinical outcomes among asthmatic children to treatment. By demonstrating these methylation markers correlate with gene expression, they can be inferred to have a functional role in asthma exacerbation. The identified methylation biomarkers may be used to provide prognostic as well as predictive information to improve patient care for asthmatic children that respond poorly to standard therapy for exacerbation, and may lead to the development of novel therapeutic strategies.
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