Scientific Core: Animal Models

科学核心：动物模型

基本信息

批准号：
10725052
负责人：
Facundo Damian Batista
金额：
$ 26.07万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
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：
2023-06-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10725052
关键词：
Adjuvant Adoptive Transfer Animal Experiments Animal Model Animals Antigens Apical Area B cell repertoire B-Cell Antigen Receptor B-Lymphocytes Bone Marrow CRISPR/Cas technology Cessation of life Communicable Diseases Development Epitopes Evaluation Feedback Formulation Frequencies Generations Genetic HIV Human Human immunodeficiency virus test Immune response Immunization Immunoglobulins Infection Infrastructure Institution Knock-in Knock-in Mouse Light Lymph Maintenance Modeling Mus Oocytes Output PTPRC gene Phase I Clinical Trials Plasma Polysaccharides Pre-Clinical Model Process Production Proteins Protocols documentation Public Health RNA Role Sampling Spleen Technology Tissues Titrations Validation adoptive B cell transfer design experimental study human monoclonal antibodies humanized mouse improved lymph nodes monomer mouse model multiple omics peripheral blood pre-clinical response tool vaccine development vaccine evaluation vaccinology

项目摘要

PROJECT SUMMARY Despite advances in treatment in recent years, HIV is still responsible for more than half a million deaths annually; new infections have, furthermore, continued to exceed the milestones set by public health institutions. Recently, a number of candidate immunogens based on either germline targeting or epitope focusing have moved to Phase 1 clinical trials. These developments in HIV vaccinology have been immensely aided by improved technology for the generation of humanized mouse models, which can be used in iterative immunogen design, early stage down-selection, and other important components of vaccine development. Among those improvements include the multiplexed CRISPR/Cas9 dual immunoglobulin heavy and light chain knockins (KI) developed by the Batista lab. With this approach, mice with B cells bearing genuine human BCRs, which can be produced in a matter of weeks. Here, the Batista lab proposes to use this approach and its expertise in animal experiments to act as the Animal Model Core (AMC) for the Multi-Omics Vaccine Evaluation (MOVE) Consortium. The AMC will develop up to six new KI lines based on MOVE's interrogation of the naïve human B cell repertoire. The AMC will furthermore contribute its existing HIV models to immunization experiments initiated by MOVE Project 1. Samples generated from murine lymph, spleen, and other tissues will then be provided to MOVE Project 2 for immunocharacterization. The AMC will act as the fulcrum of prime and boost stage immunogen, formulation, and regiment development and assessment.

项目概要尽管近年来治疗取得了进步，但艾滋病毒仍然导致超过 50 万人死亡此外，每年新感染病例继续超过公共卫生机构设定的里程碑。最近，许多基于种系靶向或表位聚焦的候选免疫原已被开发出来。 HIV 疫苗学的这些进展得到了极大的帮助。改进的人源化小鼠模型生成技术，可用于迭代免疫原设计、早期下调选择以及疫苗开发的其他重要组成部分。这些改进包括多重 CRISPR/Cas9 双免疫球蛋白重链和轻链 Batista 实验室开发的敲入蛋白 (KI) 通过这种方法，B 细胞携带真正的人类 BCR 的小鼠，巴蒂斯塔实验室建议使用这种方法及其技术，可以在几周内生产出来。动物实验方面的专业知识作为多组学疫苗评估的动物模型核心（AMC） (MOVE) 联盟将根据 MOVE 对天真的质询开发多达 6 个新的 KI 线。 AMC 将进一步将其现有的 HIV 模型用于免疫接种。 MOVE项目1发起的实验。从小鼠淋巴、脾脏和其他组织中产生的样本将然后提供给 MOVE 项目 2 进行免疫表征。加强阶段免疫原、制剂以及团的开发和评估。