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: 10154586
• 负责人: Alexandru Barbulescu
• 金额: $ 5.1万
• 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/10154586
• 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.

项目总结/文摘