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.

项目概要/摘要 感染或疫苗接种引起的高亲和力抗体滴度构成了防止再次感染的基础。 然而，预先存在的抗原特异性滴度也与次级 B 细胞反应减弱有关。 相同的抗原。这个概念被称为抗体介导的反馈，目前仍然没有明确的定义。 机械层面。阐明抗体反馈对 B 细胞克隆选择的机制和结果 需要制定针对重复遇到的保守表位的免疫策略 不断进化的病原体。 为了研究生理环境中抗体介导的反馈，我建议开发一种寡克隆 B 细胞 过继转移小鼠模型对流感血凝素上的不同表位仅具有三种特异性 （哈）。在我的初步工作中，我鉴定了三种单克隆抗体，它们与不同位点结合 哈。与此同时，我通过基因改造获得了删除浆细胞的能力。结合这两个模型 将允许从具有简化 B 细胞库的系统中去除一种特异性的免疫球蛋白。 观察去除特定抗体后 B 细胞克隆选择的结果将有助于深入了解 抗体介导的反馈运作的精确机制。 我是威尔康奈尔大学/纪念斯隆凯特林/洛克菲勒三机构项目的医学博士/博士生， 在洛克菲勒大学 Gabriel Victora 博士的实验室中进行拟议的研究。我的 长期目标是成为一名医学科学家，在患者护理和经营独立机构之间取得平衡 学术机构的研究计划。本提案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机构提供的指导 行政人员将帮助我实现我的职业目标。