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 通过感染或疫苗接种引起的高亲和力滴度构成了防止再感染的基础。 但是，先前存在的抗原特异性滴定器也与次级B细胞对 相同的抗原。这个概念称为抗体介导的反馈，在 机械水平。阐明B细胞选择的抗体反馈的机理和结果 需要制定针对保守表位的免疫策略反复遇到 不断发展的病原体。 为了在生理环境中研究抗体介导的反馈，我建议开发寡克隆B细胞 收养转移小鼠模型仅针对流感脑血谷蛋白的不同表位具有三个特异性 （哈）。在我的初步工作中，我表征了三种与不同位点结合的单克隆抗体 哈。同时，我在基因上设计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。 去除特定抗体后，观察B细胞克隆选择的结果将提供有关 抗体介导的反馈作用的确切机制。 我是Weill Cornell/Memorial Sloan Kettering/Rockefeller三机构计划的医学博士/博士学位学生， 在洛克菲勒大学的加布里埃尔·维克多拉（Gabriel Victora）博士实验室中进行拟议的研究。我的 长期目标是成为一名医师科学家，他们平衡患者护理与运行独立 学术机构的研究计划。本提案中概述的计划以及支持和 Victora博士，Nussenzweig博士，我的论文研究委员会和三机构的指导 行政教师将帮助我实现职业目标。