Exploiting and enhancing IgE-binding epitopes of the 2S albumins of peanuts and tree nuts

利用和增强花生和坚果 2S 白蛋白的 IgE 结合表位

• 批准号: 10345963
• 负责人: STEPHEN C DRESKIN
• 金额: $ 80.12万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10345963
• 关键词: 3-Dimensional; Adult; Affect; Affinity; Albumins; Allergens; Allergic Reaction; Allergy to peanuts; Amino Acids; Area; Basophils; Binding; Biological Assay; Biotin; Cashew nut; Cells; Chemistry; Child; Clinical; Clinical Research; Clinical Trials; Cross Reactions; Data; Development; Diagnostic; Enzyme-Linked Immunosorbent Assay; Epitopes; Europe; Food; Food Hypersensitivity; Health; Hypersensitivity; IgE; IgG4; Immunologics; Immunotherapy; Individual; Juglans; Measures; Mediating; Microarray Analysis; Modeling; Molecular; Molecular Conformation; Nut Hypersensitivity; Nuts; Oral; Outcome; Patients; Pattern; Pecans; Peptide Hydrolases; Peptides; Pistachio Nuts; Predictive Value; Reagent; Resistance; Sampling; Side; Streptavidin; Surface Plasmon Resonance; Technology; Testing; Therapeutic; Trees; United States; Vertebral column; analog; anti-IgE; base; clinically relevant; cost; cross reactivity; design; improved; mast cell; novel; novel diagnostics; novel strategies; omalizumab; oral immunotherapy; oral tolerance; peptide analog; screening; success; three dimensional structure

Abstract: IgE-mediated food allergy to peanuts (PN) and/or tree nuts (TN), is a major health problem in the United States, affecting approximately 4% of children and up to 2% of adults. Co-allergy among these foods is relatively common and is difficult to identify given the more common finding of co-sensitization. Recent progress with early administration of these foods and oral immunotherapy, especially in conjunction with anti-IgE have merit. Unfortunately, these approaches are not successful for all patients and, even when successful, have limitations regarding compliance and unpredictable breakthrough. There are significant, unmet needs to 1) understand the immunologic details of IgE mediated activation of mast cells by allergens from PN and TN, 2) understand the molecular basis for co-allergy among TN and between PN and TN, 3) develop improved diagnostics to identify clinically relevant peanut and tree nut allergy and 4) design new approaches to interfere with allergic reactions caused by peanuts. The overarching concept of this proposal is that the 2S albumins are the most important allergens of peanuts and tree nuts and are the key to understanding PN and TN allergy and cross-reactivity and to developing potent diagnostic and potentially therapeutic reagents. Preliminary data show that we have 1) developed a sensitive ELISA assay, 2) identified the critical amino acids within IgE-binding peptides, 3) demonstrated that conformationally constrained (3D) peptides bind IgE strongly and 4) shown that patients with PN allergy alone and PN + TN allergy identify different patterns of peptides in a microarray assay. We hypothesize that 1) we can optimize IgE binding to existing peptides and discover novel peptides with enhanced binding, 2) there are cross- reacting epitopes of PN and selected TN and 3) IgE binding to existing and novel peptides will have potential predictive value for important clinical outcomes. We propose to 1) perform positional amino acid (aa) screening to optimize binding of IgE to peptides, 2) utilize click chemistry and stapling technology to enhance IgE binding and resistance to proteases and 3) use microarray technology to assess IgE binding with well-defined samples from patients with PN, WN, PecN, CN and PisN allergy and from those undergoing clinical trials. Success in this project will establish a new intellectual framework regarding allergen/IgE interactions, describe, at least in part, the molecular basis for these co-allergies, design new diagnostics and move us along the path toward development of an oral, peptide based, treatment for peanut allergy.

抽象的： IgE介导的食物过敏对花生（PN）和/或树坚果（TN）是一个主要的健康问题 美国，约有4％的儿童和多达2％的成年人影响美国。共氧化 在这些食物中，相对普遍，很难识别出更常见的 发现共敏。这些食物和口服的早期给药的最新进展 免疫疗法，尤其是与抗IgE结合使用的功能。不幸的是，这些 对于所有患者而言，方法并非成功，即使成功也有局限性 关于合规性和不可预测的突破。有重要的，未满足的需要 1）了解过敏原对IgE介导的肥大细胞激活的免疫学细节 从PN和TN中，2）了解TN和PN之间共抗毒的分子基础 和TN，3）开发改进的诊断，以识别临床相关的花生和树坚果 过敏和4）设计新方法来干扰花生引起的过敏反应。 该提案的总体概念是2S白蛋白是最重要的 花生和树坚果的过敏原，是理解PN和TN过敏和的关键 交叉反应性并开发有效的诊断和潜在的治疗性试剂。 初步数据表明，我们有1）开发了一种敏感的ELISA分析，2）确定 IgE结合肽内的临界氨基酸，3）证明了构象的 受约束（3D）肽结合IgE，4）表明单独使用PN过敏的患者 PN + TN过敏在微阵列测定中识别不同模式的肽模式。我们 假设1）我们可以优化IgE与现有肽的结合并发现新颖 具有增强结合的肽，2）有PN的交叉反应表位和选定的TN 3）IgE与现有和新型肽的结合将具有潜在的预测价值 重要的临床结果。我们建议1）执行位置氨基酸（AA）筛选到 优化IgE与肽的结合，2）使用点击化学和钉书钉技术 增强对蛋白酶的IgE结合和抵抗力，3）使用微阵列技术评估 与PN，WN，PECN，CN和PISN过敏患者的定义明确的样品结合IgE 以及那些正在进行临床试验的人。该项目的成功将建立一个新的 有关过敏原/IgE相互作用的智力框架，至少部分地描述了 这些共振的分子基础，设计新的诊断，并沿着路径移动我们 朝着基于口服的，基于肽的花生过敏的治疗方法。