Project 1: Integrated Transcriptomics of Severity, Immunotherapy, and endotypes in Peanut Allergy

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SUMMARY - Project 1 Peanut allergy is a clinical and public health problem that affects 2.2% of children and 1.8% of adults in the United States. Individuals with peanut allergy are at daily risk for potentially life-threatening hives, angioedema, respiratory difficulty, cardiovascular compromise, gastrointestinal distress, and/or anaphylaxis following peanut ingestion. Intake of equal amounts of peanut protein may cause anaphylaxis in one person but only minor throat itching in another, despite similar allergy test profiles. Mechanisms underlying this variability in severity have been elusive. Oral immunotherapy (OIT) enables desensitization for some individuals but leads to variable gains in reaction threshold and is not effective for all. Project 1, “Integrated TRanscriptOmics of SEverity, ImmunoTherapy, and EndoTypes in Peanut Allergy” (ROSETTA), will study well-phenotyped peanut allergic children systematically undergoing double-blind, placebo-controlled oral food challenges (DBPCFC) before and after OIT as part of this application's PATHWAYS Clinical Core. Children across all levels of severity and threshold will be included. Based on threshold determined at baseline, each will receive low-dose OIT with commercial product or higher dose OIT with peanut butter trialed during our previous AADCRC. The central goal of ROSETTA is to rigorously address knowledge gaps about severity and endotypes in peanut allergy and its treatment. Research by our group and others has demonstrated the power of whole blood and single-cell transcriptomics to uncover new insights about peanut allergy. We will leverage the rich phenotypic data and biosamples collected from peanut allergic children undergoing DBPCFCs and personalized OIT within our PATHWAYS Clinical Core to achieve our aims. In Aim 1, we will lead a single cell study of reaction severity in peanut allergy. We hypothesize that dynamic changes in specific subpopulations in peripheral blood are associated with reaction severity. We will generate single cell RNA sequence time series of children undergoing DBPCFC to characterize the dynamics and gene expression of cellular subpopulations associated with reaction severity. In Aim 2, we will identify molecular networks causally shaped by peanut immunotherapy. We hypothesize that key biological processes are altered by OIT. We will find peripheral blood transcriptomic signatures associated with response to OIT and apply novel systems biology approaches to elucidate molecular networks shaped by peanut OIT and key drivers of OIT response. In Aim 3, we will discover endotypes of response to peanut immunotherapy. We hypothesize that endotypes of response to peanut OIT can be found through integrated multi-modal analysis of data from peanut allergic children undergoing OIT. We will apply endotyping frameworks we developed to data from PATHWAYS participants to identify endotypes of peanut OIT response. To ensure rigor, we have included steps to validate the results from all aims of this project. We expect that the findings from ROSETTA will exert high impact on the mechanistic understanding and therapeutic approach to peanut allergy.