Scientific Core: Animal Models

科学核心：动物模型

• 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
• 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

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 每年；此外，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。 进入一期临床试验。 HIV 疫苗学的这些发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 敲入蛋白（KI）由巴蒂斯塔实验室开发。通过这种方法，B 细胞携带真正的人类 BCR 的小鼠， 可以在几周内生产出来。在这里，巴蒂斯塔实验室建议使用这种方法及其 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） （移动）财团。 AMC 将根据 MOVE 对天真的质询开发多达 6 条新的 KI 线 人类 B 细胞库。 AMC还将进一步将其现有的HIV模型贡献给免疫接种 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 Project 2 进行免疫表征。 AMC将作为主要和次要的支点 加强阶段免疫原、配方以及团的开发和评估。