Urban children are exposed disproportionately to air pollution and indoor allergens that trigger asthma symptoms. To better address this public health problem, we propose to leverage two established and comparable urban cohorts: 1) randomized controlled trial (RCT) ?Environmental Control as Add-on Therapy in Childhood Asthma? (ECATCh) that is determining the efficacy of adding individually tailored, multi-faceted home environmental control strategy (ECS) to titration of controller medication (TCM) over 6 months among predominantly African American children with persistent asthma, and 2) observational case control ?Traffic Associated Air Pollution Asthma Study? (TAPAS) over 6 months among African American and Dominican children with and without asthma. We propose to determine the contribution of novel mitochondrial (mt) DNA biomarkers that capture responses to multiple environmental stressors, and are more sensitive to the dynamics of dysregulation, on lung function and airway inflammation. Our objective is to elucidate the dynamic interplay between reductions in multiple inflammatory urban exposures, attributable changes in mtDNA content and methylation of mitochondrial regulatory genes, and improvements in asthma outcomes over time. In two well-defined cohorts representing minority urban pediatric populations, we hypothesize that reversal of mitochondrial damage following personalized ECS and other time-related changes in multiple environmental exposures is associated with improved lung function and airway inflammation. We predict that intermediate mitochondrial biomarkers following changes in diverse personal environmental exposures may link directly to clinical outcomes. Using two repeat measures of buccal mtDNA content and buccal genomic DNA methylation of displacement loop and other regions important to mitochondrial function, we propose to: 1) Determine differences in mitochondrial biomarkers among ECATCh asthma cases, TAPAS asthma cases, and TAPAS nonasthmatic controls, and the associations of mitochondrial biomarkers with exhaled nitric oxide (eNO) and lung function within asthma cases, measured concurrently and as changes over 6 months. 2) Determine associations of repeat mitochondrial biomarkers with repeat residential measures of fine particulate matter (PM)2.5 and other asthmogenic exposures, and 3) Explore whether 6-month treatment with personalized multi-faceted ECS plus TCM vs TCM alone (i.e. ECATCh RCT group assignment) of persistent asthmatics changes mitochondrial biomarkers. Significant associations from these two cohorts will be replicated in our single-faceted environmental intervention RCT ?Mouse Allergen and Asthma Intervention Trial? (MAAIT). This proposal intends to capture the pivotal role of novel mitochondrial biomarkers in measuring the dynamic biological responses following induction and remediation of oxidative damage, triggered by a child?s changing personal environment. These results could direct more effective personalized biomarker- guided therapy for urban children with persistent asthma.
We propose to leverage two established and comparable urban cohorts of children with and without asthma each followed over 6 months to elucidate how urban exposures worsen lung function and increase airway inflammation. We propose to determine the contribution of novel mitochondrial (mt) DNA biomarkers that capture responses to multiple environmental stressors, and are more sensitive to the dynamics of dysregulation. Our premise is that we can elucidate the dynamic interplay between reductions in multiple inflammatory urban exposures, attributable changes in mtDNA content and methylation of mitochondrial regulatory genes, and improvements in asthma outcomes over time to optimize strategies to reduce risk and improve therapy for children with asthma.
