The focus of this new project is on definition of the role of the CD19-mediated signaling in B cell development, activation and effector functions. Ligation of the B-cell antigen receptor results in the phosphorylation of tyrosine residues in the CD19 cytoplasmic domain. Previous work has shown that these phosphotyrosine residues serve as docking sites for several cytoplasmic signaling molecules, including Fyn, Vav, and PI 3-kinase. The importance of CD19, and presumably CD19-mediated signaling, in B-cell development is underscored by the observation that CD19 nullizygous mice fail to respond to T cell-dependent antigens, and show a marked depletion of the B-1 B cell subpopulation. This project is intended to address the contributions of potential phosphorylation sites in the CD19 cytoplasmic domain to the function of CD19 in vivo. The approach taken will be to breed wild-type or mutant forms of human CD19 (expressed in transgenic mice) onto the CD19-/- background. The mutant CD19s contain Tyr to Phe substitutions at the putative binding sites for Vav, Fyn, or PI 3-kinase. The abilities of the mutant CD19s to reconstitute both normal B-cell development, and the antibody response of CD19-/- mice to a T-dependent antigen, NP-chicken IgG, will then be determined. In subsequent studies, the investigator will use phosphotyrosyl peptides derived from the CD19 cytoplasmic domain to affinity purify and characterize cytoplasmic molecules that associate with the phosphotyrosine sites identified as critical for B cell development and/or function in the in vivo studies. The studies proposed here should lead to significant adavances in our understanding of CD19 function and may identify target sites for the development of novel immunosuppressive agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI042265-02
Application #
2856084
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Quill, Helen R
Project Start
1998-01-01
Project End
2001-12-31
Budget Start
1999-01-01
Budget End
1999-12-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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