PROJECT ABSTRACT Asthma is a complex, heterogenous condition with both genetic and environmental factors contributing to disease. The epithelial barrier is the interface between environmental exposures and the host. Gene- environment interaction studies demonstrate that early life exposures modify genetic risks in asthma, and epigenetic changes, such as DNA methylation (DNAm) may mediate these effects. Additionally, epithelial transcriptional changes link to childhood asthma. We propose to use both of these powerful technologies to provide a mechanistic link from environmental exposure to asthma inception. We hypothesize that exposures at the epithelial barrier related to the community (air pollution, nearby green space) and the individual (microbiome) alter epithelial DNAm and transcriptional responses to promote the development of asthma. To evaluate this hypothesis, we will leverage the ECHO Cohort protocol 3.0 to determine how prenatal and early life individual and neighborhood level exposures contribute to nasal epithelial changes in infancy to promote the development of wheezing (aim 1), determine how the these exposures, including the skin microbiome, influence skin epithelial changes to promote atopic dermatitis and wheezing (aim 2), and elucidate how individual and neighborhood characteristics influence maternal nasal epigenetic changes throughout pregnancy, and how these changes relate to allergic diseases in the child (aim 4). Finally, we will follow existing ECHO participants and recruit 350 pregnant women and 50 women preconception that give birth (for a of total 400 births) into ECHO Cohort protocol 3.0 (aim 3). Importantly, throughout this proposal, we seek to disentangle factors that may underlie health disparities by identifying the mechanisms by which environmental exposures (that are often associated and conflated with race) cause asthma. We will identify precise molecular targets for diagnosis and prevention. This information can be used to (1) establish non-invasive biomarkers (from nasal or skin swabs) to identify infants at risk for asthma, (2) develop treatment strategies based on altering patterns of microbial colonization or epithelial gene expression to promote health, and (3) identify actionable exposures that underly health disparities for intervention.