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，影响着2.2%的儿童和1.8%的成年人 美国。对花生过敏的人每天都有可能患上危及生命的麻疹、血管水肿、 花生引起的呼吸困难、心血管损害、胃肠道不适和/或过敏反应 摄取。摄入等量的花生蛋白可能会引起一个人的过敏反应，但只是轻微的 另一人喉咙发痒，尽管过敏测试特征相似。这种严重性变化背后的机制 一直难以捉摸。口服免疫疗法(Oit)可以使某些人脱敏，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，“综合转录基因组学” 花生过敏的严重性、免疫治疗和内源性类型“(Rosetta)，将研究良好的表型 对花生过敏的儿童系统性地接受双盲、安慰剂对照的口服食物挑战 (DBPCFC)作为本应用程序的临床核心路径的一部分。所有国家的儿童 严重程度和阈值将包括在内。根据基线确定的阈值，每个人都将收到 在我们之前的试验中，低剂量燕麦配商用产品或高剂量燕麦配花生酱 AADCRC。Rosetta的中心目标是严格解决关于严重性和 花生过敏的内型及其治疗。我们团队和其他人的研究表明， 全血和单细胞转录组的力量，揭示了对花生过敏的新见解。我们会 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 在我们的临床核心路径中使用DBPCFC和个性化的OIT来实现我们的目标。在目标1中，我们将 领导花生过敏反应严重程度的单细胞研究。我们假设动态变化在 外周血中的特定亚群与反应严重程度有关。我们将生成单个细胞 儿童接受DBPCFC的RNA序列时间序列的动态和基因表达特征 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 是花生免疫疗法造成的。我们假设关键的生物过程会被 好的。我们将发现与OIT反应相关的外周血液转录信号，并应用新的 用系统生物学方法阐明花生籽粒形成的分子网络及其关键驱动因素 回应。在目标3中，我们将发现花生免疫治疗反应的内型。我们假设 通过对数据的综合多模式分析，可以发现对花生大蒜反应的内型。 对花生过敏的儿童正在接受OIT。我们将把我们开发的内部化框架应用于来自 参与者识别花生果仁反应内型的途径。为了确保严谨，我们包括了 验证本项目所有目标的结果的步骤。我们希望罗塞塔的调查结果将发挥作用 对花生过敏的机理认识和治疗方法产生了很大的影响。

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.