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

摘要-项目1 花生过敏是一个临床和公共卫生问题，影响2.2%的儿童和1.8%的成年人， 美国的花生过敏的个体每天都有可能发生危及生命的荨麻疹、血管性水肿， 呼吸困难、心血管损害、胃肠道不适和/或花生过敏反应 摄入摄入等量的花生蛋白可能会导致过敏反应在一个人，但只有轻微的 在另一个喉咙发痒，尽管类似的过敏试验概况。这种严重程度变化的潜在机制 一直难以捉摸口服免疫疗法（OIT）可以使一些人脱敏，但会导致 反应阈值的可变增益，并不是对所有人都有效。项目1，“集成的 花生过敏的严重性、免疫疗法和内型”（ROSETTA），将研究良好的表型 花生过敏儿童系统地接受双盲、安慰剂对照口服食物挑战 （DBPCFC）在OIT之前和之后作为该应用程序的PATHWAYS临床核心的一部分。所有儿童 将包括严重程度和阈值。根据基线时确定的阈值，每个人将接受 低剂量OIT与商业产品或更高剂量OIT与花生酱试验在我们以前的 AADCRC。ROSETTA的中心目标是严格解决有关严重性的知识差距， 花生过敏症的内源型及其治疗。我们小组和其他人的研究表明， 全血和单细胞转录组学的力量，以揭示有关花生过敏的新见解。我们将 利用从花生过敏儿童中收集的丰富的表型数据和生物样本， DBPCFC和个性化OIT在我们的路径临床核心，以实现我们的目标。在目标1中，我们 领导了一项关于花生过敏反应严重程度单细胞研究。我们假设， 外周血中的特定亚群与反应严重程度相关。我们将产生单个细胞 接受DBPCFC的儿童的RNA序列时间序列，以表征动态和基因表达 与反应严重程度相关的细胞亚群。在目标2中，我们将识别分子网络 是由花生免疫疗法造成的我们假设，关键的生物过程被改变， OIT。我们将发现与OIT反应相关的外周血转录组学特征，并将其应用于新的研究。 系统生物学方法阐明花生OIT形成的分子网络和OIT的关键驱动因素 反应在目标3中，我们将发现对花生免疫疗法的应答的内型。我们假设 对花生OIT反应的内在型可以通过对来自以下数据的综合多模态分析来发现： 花生过敏儿童接受OIT。我们将把我们开发的内型框架应用于来自 PATHWAYS参与者识别花生OIT反应的内型。为了确保严谨性，我们包括 验证本项目所有目标结果的步骤。我们预计ROSETTA的发现将发挥 对花生过敏的机制理解和治疗方法有很大影响。

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.