The broad, long-range objective of this project, since its inception, has been to understand how IgG antibodies mediate biological effects. These antibodies ligate and cluster Fc receptors for IgG (FcgR) on leukocyte plasma membranes to initiate several molecular responses that all converge to eliminate antigen, thus providing the body with a vital means of immune defense. A detailed dissection of these molecular mechanisms, such that eventually they can be manipulated to our advantage in disease, is the ultimate objective. Beginning with the simple early observation that IgG binds to cell surfaces, the field has systematically progressed to a detailed characterization of the molecules comprising the binding sites, defining a family of three classes of FcgR in humans that are central to the initiation of these cell mediated mechanisms. This project focuses on the molecular details of class I FcgR (FcgRI) where three genes encode six transcripts, one of which gives rise to the high affinity FcgRI which is now known to associate in a macromolecular complex consisting of the ITAM containing chain homodimer and three tyrosine kinases. The research plan of the project will concentrate on four prominent gaps in our understanding of the structure and function of the FcgRI complex, each comprising a specific aim. First, it will dissect further the macromolecular signaling complex concentrating on a 35 kD tyrosine phosphoprotein subunit that may be a beta-chain homologue, perhaps linking the receptor with a src kinase. Second, it will analyze the early steps of phagocytosis where it appears that pseudopod extension around an opsonized particle can be separated functionally from the internalization signal, modifying the existing paradigm. Third, it will investigate how g-chain confers high affinity for ligand upon FcgIa, FcgRIIIa, and probably FcaR, testing the likely hypothesis that FcgR dimerize in the presence of g-chain, suggesting a novel function for g-chain. Fourth, exploring a new and undescribed role for the FcgR family, it will clarify the structure and function of a splice variant of FcgRI gene B, the b2 isoform, missing the third extracellular domain, which appears to be expressed where FcgRIa is normally not found and is likely the elusive 45 kD receptor for C-reactive protein. Each of these specific aims offers unique insight into FcgR biology specifically and each has the potential to expand our understanding of receptor mechanisms generally. The experimental approaches of these aims are multidisciplinary and include the methods of immunology, cell biology, molecular genetics, and biochemistry.
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