Clinical prediction and epigenetic regulation of asthma and rhinitis

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PROJECT SUMMARY/ABSTRACT Asthma and rhinitis share a strong genetic component and are the most common chronic respiratory diseases worldwide affecting 339 million and 500 million people, respectively. Both allergic and non-allergic rhinitis are well-studied risk factors for the development of asthma, independent of atopy and IgE sensitization, and up to 80% of asthmatics have concomitant rhinitis. Conversely, asthma is also a risk factor for the development of rhinitis suggesting a common pathophysiological link between the upper and lower airways. Individuals with comorbid asthma and rhinitis are more likely to experience frequent and severe asthma exacerbations. Currently, an unmet need exists in the understanding of the comorbid development of asthma and rhinitis, including which patients are at risk and why patients with comorbid disease have increased disease severity. microRNAs (miRNAs) have emerged as important predictive biomarkers and regulators of the pathogenesis of asthma and rhinitis. However, the role of miRNA-messenger RNA (mRNA) regulatory networks in asthma with comorbid rhinitis is not known. The overall hypothesis of this K23 award proposal is that the comorbid development of asthma and rhinitis can be predicted by clinical factors and is regulated by miRNA-mRNA networks. Specific Aim 1 will evaluate the early childhood clinical prediction of the development of comorbid disease in the Vitamin D Antenatal Asthma Reduction Trial (VDAART) and Children, Allergy, Milieu, Stockholm, Epidemiology (BAMSE) cohorts and create a validated clinical prognostic tool to identify high-risk children who may benefit from early monitoring and interventions. Specific Aim 2 will identify the unique miRNA-mRNA pathways and regulatory networks in the peripheral blood that regulate asthma with comorbid rhinitis in children from the VDAART, BAMSE, and Childhood Asthma Management Program (CAMP) cohorts to identify candidate miRNAs and biological pathways that may serve as future targets of miRNA-based therapies and biomarkers. Specific Aim 3 will prospectively validate the miRNA-mRNA signature of asthma with comorbid rhinitis across the peripheral whole blood and local nasal epithelium in subjects recruited from Brigham and Women’s Hospital to identify the shared and tissue-specific pathogenic pathways in the peripheral blood and local primary airway tissue. Through this K23 award proposal, the candidate will complete an integrated plan of mentorship, coursework, conferences, patient-oriented research, statistical and computational analyses, manuscript submissions, and R01 grant preparation. She will develop new knowledge and skills in clinical, translational, and computational research and generate new hypotheses and data that will provide the basis for future independent lines of investigation. Funding from this administrative supplement will support a bioinformatics programmer and clinical research coordinator to help accelerate the candidate’s return to productivity after a critical life event and enable her to substantially progress toward her goal of becoming a successful independent investigator in the epidemiology and epigenetics of asthma and allergic diseases.