Pulmonary epithelial barrier and immunological functions at birth and in early life - key determinants of the development of asthma?.

Inception of asthma, the commonest chronic childhood disease, is determined by early life events including aeroallergen sensitization, bacterial and viral infections. Reduction in lung function, established by age six, is sustained throughout life. Not all wheezy children develop asthma, and mechanisms underlying progression of preschool wheeze to asthma are unknown. Airway epithelial function and associated immune responses are key drivers of this process in established asthma. Mouse models ind icate that the microbiota directs immune development and skews allergic responses. The relationship between epithelial and immune development, and their interactions with the airway microbiota in preschool children is unknown. We will profile airway epithelial cells from babies and young children and compare to severe paediatric asthma, in order to identify gene signatures that stratify controls, wheezers and asthmatics, validating this in established birth cohorts. We will investigate the evol ution of epithelial function, immune responses and airway microbiome following allergen, viral and bacterial exposures. We will determine the molecular mechanisms whereby epithelial-immune-microbial-gene interactions are skewed towards asthma rather than resolution. Our vision is to understand what initiates asthma and facilitate development of biomarkers predicting progression of preschool wheeze to asthma. Our over-arching goal is asthma prevention and improvement of lifelong lung health.