The revised research project proposal in molecular immunology is directed at establishing the mechanisms which control the stage-specific activation and the tissue-specific expression of genes in B cell development. The studies proposed here are based on the premise that developmentally- regulated and tissue restricted gene expression is mediated by the release from negative controls in conjunction with the appearance of positive regulatory factors. Ongoing studies on the processes and factors in immunoglobulin kappa light chain gene activation in LPS-induced pre-B cells are focused on kappa silencer elements and a recently-identified kappa intron enhancer site required for LPS induction. New studies are directed at defining the role of the kappa 3'-enhancer in interferon-gamma (AWN- gamma) induction of kappa gene expression. Dominant negative control mechanisms (i.e., silencers) appear to play an major role in controlling awn' enhancer activity during maturation of pre-B cells to B cells and in IFNgamma-induction. While these studies are focused on the molecular mechanisms controlling kappa light chain gene activation in pre-B cell maturation, the findings from this research impact directly on the activation of genes in inflammation. The inducers studied here (i.e., LPS and IFNgamma) are potent mediators of systemic and local inflammatory responses. Insights into the molecular features controlling kappa gene activation by these mediators should provide new strategies for interceding in septic shock and other pathological inflammatory conditions caused by inappropriate cell activation.
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