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.

项目摘要 迫切需要开发新的疫苗接种策略，以诱导抗体， 靶向复杂微生物上的相关表位。此外，允许控制 应答幼稚或记忆B细胞的数量和精细特异性库将 为各种变异病毒的新疫苗设计提供了燃料。该项目的中心是 B细胞抗原受体（BCR）与Notch2共结合假说 受体将放大幼稚和记忆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， 细胞的反应和这些细胞经历的增殖事件的数量。到 测试我们的假设，我们将产生独特的马赛克纳米粒子的基础上免疫原性， 和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共接合是否将幼稚克隆致敏至靶向 类似原生的Env变体？，和2）BCR+Notch2共接合在记忆B细胞上吗 增加他们对GC和PC池的贡献？这些研究将提供独特的， 需要深入了解BCR信号阈值的潜在利用， 疫苗设计