The Notch Pathway in Antigen Design

抗原设计中的Notch途径

• 批准号: 10575892
• 负责人: David M Allman
• 金额: $ 26.4万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-18 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10575892
• 关键词: Affinity; Antibodies; Antibody Affinity; Antibody Response; Antibody titer measurement; Antigens; B Cell Proliferation; B cell repertoire; B-Cell Antigen Receptor; B-Lymphocytes; Binding; Cells; Clonal Expansion; Clone Cells; Complement; Complement 3d; Complement 3d Receptors; Complex; Data; Epitopes; Event; Excision; Frequencies; Glycoproteins; HIV; HIV Antibodies; HIV envelope protein; Humoral Immunities; Immunization; In Vitro; Infection; Label; Ligands; Ligation; Membrane; Memory; Memory B-Lymphocyte; Microbe; Mus; Mutate; Pathway interactions; Physiologic pulse; Plasma Cells; Play; Polysaccharides; Protocols documentation; Publishing; Receptor Activation; Receptor Signaling; Role; Secondary to; Serology; Serum; Specificity; Testing; Vaccine Design; Variant; Virus; Work; design; experience; glycosylation; immunogenic; immunogenicity; improved; in vivo; insight; mosaic; nanoparticle; neutralizing antibody; notch protein; novel vaccines; receptor; response; stem; tool; vaccination strategy; vaccine strategy; vaccine-induced immunity

Project summary There is an urgent need to develop new vaccination strategies that induce antibodies that target relevant epitopes on complex microbes. Moreover, approaches that allow control of the number and fine specificity repertoire of responding naïve or memory B cells would fuel new vaccine designs for a variety of mutating viruses. This project centers on the hypothesis that co-engagement of the B cell receptor (BCR) for antigen with the Notch2 receptor will amplify responses by naïve and memory B cells. This hypothesis builds on preliminary data showing that BCR+Notch2 co-stimulation increases both number of B cells that respond and the number of proliferative events experienced by these cells. To test our hypothesis, we will generate unique mosaic nanoparticles based on immunogenic and sub-immunogenic variants of the HIV envelop (Env) antigen. We will answer the following questions: 1) Does BCR+Notch2 co-engagement prime naïve clones to target native-like Env variants?, and 2) Does BCR+Notch2 co-engagement on memory B cells increase their contribution to GC and PC pools? These studies will provide unique and needed insights into the potential exploitation of BCR signaling thresholds in emerging vaccine design.

项目概要 迫切需要开发新的疫苗接种策略来诱导抗体 靶向复杂微生物上的相关表位。此外，允许控制的方法 响应幼稚或记忆 B 细胞的数量和精细特异性库 为针对各种变异病毒的新疫苗设计提供动力。该项目的中心是 假设抗原的 B 细胞受体 (BCR) 与 Notch2 共同接合 受体将放大幼稚 B 细胞和记忆 B 细胞的反应。这个假设建立在 初步数据显示 BCR+Notch2 共刺激增加了 B 的数量 做出反应的细胞以及这些细胞经历的增殖事件的数量。到 检验我们的假设，我们将生成基于免疫原性的独特镶嵌纳米颗粒 以及 HIV 包膜 (Env) 抗原的亚免疫原性变体。我们将回答 以下问题：1) BCR+Notch2 是否与初始幼稚克隆共同接合以靶向 类似天然的 Env 变体？以及 2) BCR+Notch2 是否与记忆 B 细胞共同参与 增加对 GC 和 PC 池的贡献？这些研究将提供独特且 需要深入了解新兴市场中 BCR 信号阈值的潜在利用 疫苗设计。