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

基本信息

批准号：
10685312
负责人：
STEPHEN C DRESKIN
金额：
$ 68.29万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
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/10685312
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 clinically relevant cost cross reactivity design improved mast cell novel novel diagnostics novel strategies omalizumab oral immunotherapy oral tolerance screening success three dimensional structure

项目摘要

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 介导的花生 (PN) 和/或坚果 (TN) 食物过敏是人类的一个主要健康问题美国，影响约 4% 的儿童和高达 2% 的成人。联合过敏这些食物中比较常见，并且由于较常见而很难识别共同敏化的发现。早期施用这些食物和口服的最新进展免疫治疗，特别是与抗 IgE 联合治疗具有优点。不幸的是，这些方法并非对所有患者都成功，即使成功，也有局限性关于合规性和不可预测的突破。有大量未满足的需求 1) 了解过敏原 IgE 介导的肥大细胞激活的免疫学细节从PN和TN，2）了解TN之间和PN之间共同过敏的分子基础和 TN，3) 开发改进的诊断方法来识别临床相关的花生和坚果过敏；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坚果的过敏原是了解 PN 和 TN 过敏的关键交叉反应并开发有效的诊断和潜在的治疗试剂。初步数据表明，我们 1) 开发了一种灵敏的 ELISA 检测方法，2) 鉴定了 IgE 结合肽中的关键氨基酸，3) 证明构象上约束 (3D) 肽强烈结合 IgE，4) 表明仅患有 PN 过敏的患者 PN + TN 过敏可在微阵列测定中识别不同的肽模式。我们假设 1) 我们可以优化 IgE 与现有肽的结合并发现新的结合增强的肽，2) PN 和选定的 TN 存在交叉反应表位 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) 进行位置氨基酸 (aa) 筛选优化 IgE 与肽的结合，2) 利用点击化学和装订技术增强 IgE 结合和对蛋白酶的抵抗力，3) 使用微阵列技术来评估 IgE 与 PN、WN、PecN、CN 和 PisN 过敏患者的明确样本结合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关于过敏原/IgE 相互作用的知识框架，至少部分地描述了这些联合过敏的分子基础，设计新的诊断方法并推动我们沿着这条道路前进致力于开发基于肽的口服花生过敏治疗方法。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Peptide immunotherapy for aeroallergens.

针对空气过敏原的肽免疫疗法。

DOI：
发表时间：
2023-07-01
期刊：
影响因子：
2.8
作者：
Midoro;Schein, Catherine H
通讯作者：
Schein, Catherine H

使用过敏蛋白结构数据库 (SDAP) 工具和 D-Graph 识别相似的过敏原和潜在的交叉反应区域。

DOI：
发表时间：
2024
期刊：
影响因子：
0
作者：
Schein; Catherine H
通讯作者：
Catherine H

Plant-based enveloped Ara h 2 bioparticles display exceptional hypo-allergenicity.

基于植物的包膜 Ara h 2 生物颗粒表现出卓越的低过敏性。

DOI：
发表时间：
2023-05
期刊：
影响因子：
0
作者：
Castenmiller, C;Stigler, M;Kirpas, M E;Versteeg, S;Akkerdaas, J H;Pena;Blokhuis, B R;Dreskin, S C;Auger, L;Desgagnés, R;Martel, C;Mirande, L;Morel, B;Roberge, J;Stordeur, V;Tropper, G;Vézina, L P;Gomord, V;de Jong, E C;Re
通讯作者：
Re

Alanine Scanning of the Unstructured Region of Ara h 2 and of a Related Mimotope Reveals Critical Amino Acids for IgE Binding.

对 Ara h 2 和相关模拟表位非结构化区域的丙氨酸扫描揭示了 IgE 结合的关键氨基酸。

DOI：
发表时间：
2023-11
期刊：
影响因子：
5.2
作者：
Canon, Nicole;Schein, Catherine H;Braun, Werner;Negi, Surendra S;Chen, Xueni;Kulis, Michael D;Kim, Edwin H;Pathy, Vidya;Pozzoli, Marina;Liu, Weimin;Dreskin, Stephen C
通讯作者：
Dreskin, Stephen C

The Effector Function of Allergens.

过敏原的效应器功能。