Molecular control of germinal center selection and affinity maturation

Information

  • Research Project
  • 10212931
  • ApplicationId
    10212931
  • Core Project Number
    R01AI139117
  • Full Project Number
    5R01AI139117-04
  • Serial Number
    139117
  • FOA Number
    PAS-15-055
  • Sub Project Id
  • Project Start Date
    8/15/2018 - 5 years ago
  • Project End Date
    7/31/2023 - 10 months ago
  • Program Officer Name
    FERGUSON, STACY E
  • Budget Start Date
    8/1/2021 - 2 years ago
  • Budget End Date
    7/31/2022 - a year ago
  • Fiscal Year
    2021
  • Support Year
    04
  • Suffix
  • Award Notice Date
    8/6/2021 - 2 years ago
Organizations

Molecular control of germinal center selection and affinity maturation

PROJECT SUMMARY/ABSTRACT Germinal centers (GCs) are site of antibody somatic hypermutation (SHM) and affinity maturation, and are therefore essential for effective humoral immune responses to pathogens. Efficient affinity maturation in GCs requires that B cells cycle between two different cell states, associated with distinct microanacomical compartments: (i) a ?proliferation? mode, when B cells divide and undergo SHM, which takes place in the dark zone (DZ) of the GC; and (ii) a ?selection? mode, when mutated B cells compete with each other based on their affinity for antigen, which takes place in the GC light zone (LZ). While our previous work defined the transcriptional programs broadly associated with LZ and DZ states, our understanding of how cells decide when to transition between one state and another remains incomplete. For example, we do not understand the signals that trigger DZ B cells to stop proliferating and return to the LZ, nor do we know whether LZ and DZ cells can be further parsed into additional transcriptionally distinct states that associated with different stages of GC selection. Here, we propose to combine in vivo models of synchronized GC selection with novel mouse genetic models, treatment with signaling inhibitors, and single-cell mRNA sequencing to determine the full complement of GC transcriptional states and to address how these states are associated with GC selection. A clear definition of these programs will improve our understanding of how GC B cell selection and affinity maturation are controlled, with implications for vaccine design. Moreover, determining how GC B cell proliferation is controlled will further our understanding of GC-derived B cell lymphomas, which rely on similar mechanisms as GCs to achieve sustained proliferation.

IC Name
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
  • Activity
    R01
  • Administering IC
    AI
  • Application Type
    5
  • Direct Cost Amount
    268151
  • Indirect Cost Amount
    186365
  • Total Cost
    454516
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    855
  • Ed Inst. Type
    GRADUATE SCHOOLS
  • Funding ICs
    NIAID:454516\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    CMIB
  • Study Section Name
    Cellular and Molecular Immunology - B Study Section
  • Organization Name
    ROCKEFELLER UNIVERSITY
  • Organization Department
    MICROBIOLOGY/IMMUN/VIROLOGY
  • Organization DUNS
    071037113
  • Organization City
    NEW YORK
  • Organization State
    NY
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    100656399
  • Organization District
    UNITED STATES