(taken from application) This application outlines the research and career plan proposed by Dr. Melanie Sherman concerning the investigation of the role of mast cells in immunity to extracellular pathogens. These microbes typically induce a Th2-type immune response, which is characterized by the generation of an effective antibody response against bacterial and parasitic antigens. The cytokine interleukin 4 (IL-4) is essential for this process. Dr. Sherman investigated the pathway involved in the presentation of microbial pathogens to T cells for her graduate work; during her postdoctoral fellowship she explored the cell-specific regulation of IL-4 expression. IL-4 is strictly controlled, in fact only a subset of T cells and cells of the mast cell/basophilic lineage express this cytokine. Although T cells require prior exposure to IL-4 in order to acquire an IL-4-producing phenotype, Dr. Sherman discovered that mast cell IL-4 production is much less discriminate. It is possible that the release of IL-4 from mast cells early at an early stage of infection can induce or expand T cells for an effective late-phase Th2 response. Too much IL-4 can cause tissue damage, however, so the transcription of excess IL-4 by mast cells appears to be controlled by a negative feedback loop involving a mast cell-specific isoform of the transcription factor STAT6. In this application experiments are proposed to clone and characterized this STAT6 isoform, to determine the cellular signaling events leading to its activation, and to explore the effect of mast cell IL-4 on Th2 differentiation. This research will be performed at Emory University which houses state-of-the-art facilities and programs that foster interactions with other researchers, including the outstanding scientists at the Centers for Disease Control and Prevention.
