The long term objective of this research is to reduce the incidence of human reproductive failures through the identification of previously unknown or unsuspected reproductive toxins and through an understanding of the mechanisms by which they interfere with developmental processes. Based on previous studies in this lab and the work of others we propose to study one possible cause of reproductive failure involving the following sequence: (I) pollutants act on basement membranes in the maternal organism causing the release of the membrane specific protein laminin, (II) anti-laminin antibodies are produced and infiltrate the lumen of the uterus and (III) early embryos fail to develop because anti- laminin antibodies block the uptake and/or utilization of nutrient proteins by the endodermal cells of visceral yolk-sac. Studies are proposed along three related lines of research. First, the HgCl2-Brown Norway rat model for glomerulonephritis will be used to study anti-laminin auto-immunity and reproductive failure. Second, the laminin immunological determinants responsible for embryo toxicity will be identified by the use of polyclonal antibodies made against specific laminin fragments and by the use of monoclonal antibodies produced against certain laminin domains. Finally, through the use of these antibodies the mechanism of anti- laminin embryo toxicity will be determined and provide the basis for treatment of reproductive failure associated with autoimmunity to laminin and other basement membrane proteins.
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