The goal of this study is to gain a better understanding of the molecular mechanisms by which the human homolog of the MHC class I related receptor, FcRn, functions. Almost all of our studies to date have been carried out using the related mouse FcRn (mFcRn) and we now wish to extend these analyses to the human system. Recent experiments indicate that mFcRn not only transfers IgGs from mother to young but also regulates serum IgG levels. Similarly, the available data suggest that human FcRn (hFcRn) mediates the transfer of IgGs across the maternofetal barrier and also maintains serum IgG homeostasis. Thus, defects in hFcRn at either the expression or functional level may result in clinical symptoms, and it is our longer-term goal to investigate a possible role for hFcRn in human disease. The hypotheses that drive this study are: first, that the interaction of hFcRn with hlgGs resembles the interaction of rodent FcRn with cognate ligand at the molecular level. Second, that hFcRn mediates maternofetal transfer of IgGs across the placenta. Third, that peptide ligands, which bind to hFcRn, can be isolated and these ligands will be useful reagents to analyze hFcRn function. Fourth, that the localization and trafficking of hFcRn in an in vitro transfection system are consistent with its proposed functions in vivo. These hypotheses will be tested by carrying out the following specific aims: 1) map the interaction site for hFcRn on hlgGs; 2) map the interaction site for hlgGs on hFcRn; 3) isolate peptides that bind to hFcRn and to analyze their in vitro and in vivo properties; and 4) carry out studies to analyze the trafficking of hFcRn. The information that we hope to gain from this study should be of value in not only understanding the molecular basis of diseases where a defect in hFcRn may be involved, but also in broadening our current knowledge of transcytotic receptors
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