Immunologic Basis of Resistance and Hypersensitivity

Brigham And Women'S Hospital, Boston MA

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Abstract

DESCRIPTION (provided by applicant): This continuation of an established training program emphasizes the techniques and concepts of cellular and molecular biology applied to fundamental studies of the adaptive immune and inflammatory responses. The faculty of the program is uniquely competent to conduct research and training in the afferent and efferent pathways of the host responses initiated by immune and innate stimuli, including the following areas: signal transduction via the TCR and the FcepsilonRI pathways, respectively, including the role of various protein kinases and adaptor proteins such as the Cbl family; counterregulatory receptors such as gp49B 1 and the leukocyte immunoglobulin-like receptors (LIRs) with ITIM motifs to attenuate the activation of mouse mast cells and human leukocytes; RNA-binding proteins such as TIA and TIAR, that serve as translational repressors 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; functional and structural characterization of the gamma delta receptor; antigen processing and presentation involving CD1molecules with a focus on non-protein antigens recognized by T cells; characterization of the components of the mast cell secretory granule protease/proteoglycan complex and analysis of their in situ regulation in gene disrupted mice and of their actions by administration of recombinant human and mouse proteases to mice; integrin-counter receptor 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, and transcriptional regulation of LTC4 synthase and PGD2 synthase; in situ studies of the physiologic/pathobiologic functions of alphaEbetaB7, gp49B1, LTC4 synthase, PGD2 synthase, IP-10, and BLTR1 with gene-disrupted strains on both BALB/c and B6 backgrounds. 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 supplement the training. Support is again requested for eight postdoctoral trainees having either a M.D. or Ph.D. degree or both and one predoctoral trainee.