Description) The major specific aims for this grant are: 1) Define mechanisms involved in signal transduction and the regulation of gene expression in cells of the immune system. Identify genes whose expression changes in response to differentiation or activation signals. Characterize genetic defects in signal transduction mutants that fail to respond to inflammatory cytokines or other immunostimulatory agents. Develop a second FACS-detectable reporter gene system and establish methods for independently measuring the expression of this gene and the expression of the Lac-Z (B-galactosidase) reporter gene in the same cell. Define the pathways through which oxidants and antioxidants regulate the expression of genes stimulated by tumor necrosis factor-alpha (TNF-a) and other inflammatory cytokines; 2) Further define immunoglobulin structure/function relationships. Select and characterize additional hybridoma variants whose binding affinities differ from a parental antidigoxin monoclonal antibody whose structure has now been solved by X-ray crystallography. Explore the functional and developmental characteristics of the CD5 and other B cell subsets in relation to the model of the evolutionary layered immune system proposed by the applicant; and 3) Create innovative software and hardware that will bring new and improved capabilities to the FACS and make the instrument easier to use for complex sorting and analysis experiments.
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