The Notch Pathway in Antigen Design

抗原设计中的Notch途径

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要迫切需要制定影响抗体的新疫苗策略针对复杂微生物的相关表位。此外，允许控制的方法响应幼稚或记忆B细胞的数量和精细的特异性库将为各种突变病毒设计新的疫苗设计。该项目以假设B细胞受体（BCR）与Notch2共同参与抗原受体将通过幼稚和记忆B细胞扩大反应。这个假设建立在初步数据表明BCR+Notch2共刺激增加了B的两个数量响应的细胞以及这些细胞经历的增生剂事件的数量。到检验我们的假设，我们将基于免疫原性生成独特的镶嵌纳米颗粒和HIV包膜（ENV）抗原的亚不良变异。我们将回答以下问题：1）bcr+Notch2共同启用PrimeNaïve克隆以靶向类似天然的Env变体？和2）BCR+NOTCH2是否在记忆B细胞上共同参与增加他们对GC和PC池的贡献？这些研究将提供独特的和需要深入了解出现的BCR信号传导阈值的潜在开发疫苗设计。