Investigating the Effect of Antibody Mediated Feedback on B Cell Clonal Selection

研究抗体介导的反馈对 B 细胞克隆选择的影响

• 批准号: 10359063
• 负责人: Alexandru Barbulescu
• 金额: $ 5.18万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-15 至 2025-01-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10359063
• 关键词: Ablation; Address; Adoptive Transfer; Affect; Affinity; Animal Model; Antibodies; Antibody Affinity; Antibody titer measurement; Antigen-Antibody Complex; Antigens; Autoimmune Diseases; B cell repertoire; B-Cell Antigen Receptor; B-Lymphocytes; Binding; Biological Assay; Biological Models; Bone Marrow; CRISPR/Cas technology; Cells; Cellular biology; Clone Cells; Complex; Data; Diphtheria Toxin; Electron Microscopy; Engineering; Enzyme-Linked Immunosorbent Assay; Epitopes; Equilibrium; Excision; Faculty; Fc Receptor; Feedback; Genetic Engineering; Goals; Hemagglutinin; Home; Human; Immune response; Immune system; Immunization; Immunoglobulins; Immunologic Memory; Immunologics; Infection; Influenza; Influenza Hemagglutinin; Institution; Interferometry; Knock-in Mouse; Knowledge; Laboratories; Light; Maps; Masks; Mediating; Mentorship; Modeling; Monoclonal Antibodies; Mouse Strains; Mus; Outcome; Output; Patient Care; Physicians; Physiological; Plasma Cells; Play; Population; Reaction; Regimen; Regulation; Reproducibility; Research; Role; Running; Scientist; Serum; Signal Transduction; Site; Specificity; Structure; Structure of germinal center of lymph node; System; Testing; Toxin; Universities; Vaccination; Work; adaptive immunity; adoptive B cell transfer; arm; career; cryogenics; design; doctoral student; human pathogen; improved; in vivo; in vivo Model; innovation; insight; loss of function; mouse model; pathogen; programs; receptor; response; secondary lymphoid organ; tool; vaccination strategy; vaccine response; zygote

Project Summary/Abstract High affinity antibody titers elicited by infection or vaccination form the basis for protection against reinfection. However, preexisting antigen-specific titers are also associated with diminished secondary B cell responses to the same antigen. This concept, termed antibody mediated feedback, remains poorly defined at the mechanistic level. Elucidation of the mechanisms and outcomes of antibody feedback on B cell clonal selection is required to develop immunization strategies that target conserved epitopes on repeatedly encountered evolving pathogens. To study antibody mediated feedback in a physiologic setting, I propose to develop an oligoclonal B cell adoptive transfer mouse model with only three specificities to different epitopes on influenza hemagglutinin (HA). In my preliminary work, I have characterized three monoclonal antibodies that bind to distinct sites on HA. In parallel, I have genetically engineered the ability to delete plasma cells. Combining these two models will allow for the removal of immunoglobulin of one specificity from a system with a simplified B cell repertoire. Observing the outcomes of B cell clonal selection upon removal of specific antibodies will provide insight into the precise mechanism by which antibody mediated feedback operates. I am an MD/PhD student at the Weill Cornell/Memorial Sloan Kettering/Rockefeller Tri-Institutional Program, performing the proposed research in the laboratory of Dr. Gabriel Victora at The Rockefeller University. My long-term goal is to become a physician scientist who balances patient care with running an independent research program at an academic institution. The plan outlined in this proposal, along with the support and mentorship provided by Dr. Victora, Dr. Nussenzweig, my thesis research committee, and the Tri-Institutional administrative faculty will help me achieve my career goals.

项目摘要/摘要 感染或接种疫苗引起的高亲和力抗体滴度是预防再次感染的基础。 然而，先前存在的抗原特异性滴度也与次级B细胞对 同样的抗原。这一概念被称为抗体介导的反馈，目前仍没有明确的定义。 机械化水平。抗体反馈在B细胞克隆选择中的作用机制和结果的阐明 需要开发针对重复遇到的保守表位的免疫策略 不断进化的病原体。 为了在生理环境中研究抗体介导的反馈，我建议开发一种寡克隆B细胞 流感血凝素不同表位只有三种特异性的过继转移小鼠模型 (HA)。在我的初步工作中，我已经鉴定了三种与不同部位结合的单抗 哈哈。同时，我通过基因工程获得了删除浆细胞的能力。将这两种模式结合起来 将允许从具有简化的B细胞谱系的系统中去除一种特异性的免疫球蛋白。 观察B细胞克隆选择在清除特定抗体后的结果将有助于深入了解 抗体介导的反馈作用的确切机制。 我是威尔·康奈尔/纪念斯隆·凯特林/洛克菲勒三所学院的医学博士/博士生， 在洛克菲勒大学加布里埃尔·维克托拉博士的实验室进行拟议的研究。我的 长期目标是成为一名内科科学家，在病人护理和运营独立医院之间取得平衡 学术机构的研究项目。这项建议中概述的计划，以及支持和 由Victora博士、Nussenzweig博士、我的论文研究委员会和三大机构提供的指导 行政学院将帮助我实现我的职业目标。