Transcription Regulation by B-Cell Receptor Signaling

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): Signals discharged from the B-cell antigen
receptor (BCR) control B-cell physiological responses by regulating specific
transcription factors and their downstream target genes. Our long-term goal is
to understand the intracellular signal transduction pathways that regulate
genes under BCR control. Transcription factor NF-kappaB is coupled to the BCR
and essential for B cell survival and proliferation. However, the mechanisms
that regulate the BCR/NF-KB axis remain poorly understood. The applicant's
laboratory has recently discovered that Bruton's tyrosine kinase (BTK),
phospholipase C-gamma2 (PLC-gamma2), and IkappaB kinase (IKK) are all integral
components of this pathway. Importantly, interference with NF-kappaB signaling
at the level of BTK leads to B cell immunodeficiencies in mice (X-linked
immunodeficiency; xid) and humans (X-linked agammaglobulinemia; XLA). This
grant application is predicated on the central hypothesis that BTK stimulates
PLC-gamma2 phosphorylation and activation, which leads to calcium mobilization
and protein kinase C (PKC) induction. In turn, these second messengers act in
concert to stimulate the effectors that activate BCRresponsive IRK complexes.
To test the central hypothesis, we propose an integrated series of biochemical
studies with mutant B cells that lack either BTK, PLC-gamma2, or IKK. Studies
described in Specific Aim 1 will elucidate the biochemical interplay between
BTK and PLC-gamma2 as well as the PKC isoforms that affect IKK function in
response to BCR engagement. Specific Aim 2 experiments will define the
molecular size, phosphorylation status, and subunit composition of IKK
complexes under BCR control. In Specific Aim 3, studies are proposed to
identify the precise BCR-inducible modifications to IKK that lead to NF-kappaB
activation. Results from the proposed studies will uncover novel regulatory
steps in the BCR/NF-kappaB axis that are crucial for the development of an
adaptive immune response. Identification of these important missing links may
reveal new immunotherapeutic targets for intervention in B-cell deficiency
diseases such as XLA.
StatusFinished
Effective start/end date9/30/015/31/07

Funding

  • National Institute of Allergy and Infectious Diseases: $226,500.00
  • National Institute of Allergy and Infectious Diseases: $50,475.00
  • National Institute of Allergy and Infectious Diseases: $204,525.00
  • National Institute of Allergy and Infectious Diseases: $204,458.00
  • National Institute of Allergy and Infectious Diseases: $226,500.00

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