Project Summary/Abstract Asthma is the #1 chronic disease in childhood: prevention is an unmet need and pressing priority. We are conducting the first randomized, double-blind, placebo controlled trial in 200 high risk children 2-3 years of age to determine whether 2 years of treatment with omalizumab (anti-IgE) will prevent asthma and/or diminish asthma severity 2 years after treatment is stopped. Our hypothesis revolves around the role that IgE plays in the development of persistent asthma by catalyzing allergic type 2 driven recurrent wheezing and augmenting virally-induced exacerbations in susceptible young children. Recent studies have demonstrated the feasibility and power of using new and novel systems-scale network analysis of transcriptional pathways and epigenetic signatures to assess airway responses in readily obtained nasal samples. We hypothesize that patients who respond to anti-IgE may have upregulated expression of genes related to antiviral responses, epithelial cell structure and barrier integrity. This project will allow us to complete the trial and use state of the art epigenomic and transcriptomic techniques with integrative approaches to explore this hypothesis and examine the role of specific alterations in Treg cells and antigen-specific T cells in transducing clinical responses seen in the trial. Our first aim is to complete the trial to assess whether interfering with environmental allergen IgE-mediated immunological responses can prevent or moderate a progression to asthma in susceptible children. Our second aim is to examine the relationship between anti-viral and epithelial integrity pathways and the response to anti-IgE through DNA methylation and transcriptomic signatures and associated effects on Type 2 inflammation, wheezing episodes, asthma, and asthma severity. We will extend our findings to include single- cell transcriptional profiling in a subset to more fully inform the cellular sources of bulk transcriptome responses and provide important molecular details about individual cell heterogeneity and rare cell populations that relate to clinical responsiveness and clinical outcomes. We will integrate multi-omic and clinical data and perform analyses to define the combined transcriptomic and epigenetic changes underlying response to anti-IgE treatment and the persistence or resolution of benefit (including asthma outcome) following cessation of therapy. These signatures will provide comprehensive mechanistic insights on clinical treatment effects of responders vs. non-responders, and specific DNA methylation and gene expression molecular pathways that impact study outcomes and elucidate the disease modifying effects of anti-IgE. Differences in these profiles could provide potential biomarkers predictive of clinical and immunologic response to anti-IgE. This study is potentially paradigm shifting – regardless of the outcomes of the trial, we will gain considerable knowledge on the pathophysiology of the disease a...