This continuation of an established training program emphasizes the techniques and concepts of cellular and molecular biology applied to fundamental studies of innate and adaptive immune inflammatory responses. The faculty of the program is highly competent to conduct research and training in the afferent and efferent pathways of host responses, including the following areas: signal transduction via TCR and FceRI pathways;various protein kinases and adaptor proteins;counterregulatory receptors such as gp49B1 and the leukocyte immunoglobulin-like receptors (LIRs) with ITIM motifs to attenuate the activation of mouse mast cells and PMNs and human basophils and eosinophils;RNA-binding proteins such as TIA and TIAR, that serve as translational repressers in the balance between cell survival and apoptosis;intracellular vesicular traffic from ER to Golgi and in the endosome pathway;molecular analysis of the immune response in human and murine systems in terms of function and regulation of T cell-derived cytokines and identification of genetic programs and activation events in T helper cell (Th1/Th2) differentiation;molecular mechanisms in IgE biosynthesis and in primary immunodeficiency diseases;antigen processing and presentation involving CD1 molecules with a focus on non-protein antigens recognized by NKT cells;characterization of the components of the mast cell secretory granule protease/proteoglycan complex and analysis of their in situ function as assessed in gene disrupted mice;integrin-ligand and chemokine receptor-ligand interactions in the homing of T cells and of mast cell lineage progenitors;cytokine regulation of eicosanoid biosynthesis in human and mouse culture-derived mast cells;transcriptional regulation of LTC4 synthase and PGD2 synthase;analysis of the lineage progression and tissue distribution of bipotent mast cell/basophil progenitors and their progeny;utilization of strains lacking biosynthesis of LTC4 (LTC4 synthase null) or receptor-mediated cysteinyl leukotriene signaling (CysLTI and CysLT2 null) to characterize acute and chronic innate and adaptive immune contributions to pulmonary fibrosis and allergic and autoantibody-mediated inflammation, respectively. Although the primary strength of the program resides in the direct and individual character of the interaction in the laboratory between each Fellow and the responsible faculty member(s), substantial didactic experiences within the medical school environment supplement the training. Support is again requested for eight postdoctoral trainees having either a MD or PhD degree or both and one predoctoral trainee. Underlying allergic, asthmatic and autoimmune diseases are activated innate and adaptive host inflammatory pathways that are modulated by genetic and environmental determinants. Characterization of these proinflammatory pathways allows for therapeutic approaches based on targeted intervention.
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