The long-term objective of this research continues to focus on reducing the incidence of human reproductive failures through (I) the identification of previously unknown and unsuspected reproductive toxins and (II) through an understanding of the mechanisms by which they interfere with developmental processes. Based on previous studies in this lab as well as those from other labs our research has been directed at testing an hypothesis of reproductive failure based on the following sequence: (I) a pollutant acting on basement membranes in organs of a potential mother cause tissue breakdown and the release into the circulation of basement membrane proteins such as the highly antigenic protein, laminin, (II) antilaminin autoantibodies are then produced and pass into the lumen of the uterus as IgG and IgA immunoglobulins and (III) early embryos fail to develop because the laminin antibodies block such processes as the uptake and/or utilization of nutrient proteins by the yolk-sac. Based on the progress that has been made, we now propose to consider three related lines of research. First, we will identify embryo toxic laminin epitopes using antibodies raised in monkeys against synthetic laminin peptides, monoclonal antibodies against laminin and antilaminin antibodies from women with histories of spontaneous abortions. Next, we will use three distinct approaches to study three aspects of embryo toxicity related to mechanisms of antilaminin antibody action. This will include studies of the interactions between laminin antibodies and methionine in vitro, feeding dietary supplement of methionine to high risk pregnancy monkeys and determining the embryo toxicity of IgG and IgA immunoglobulins in uterine secretions. Finally, we propose to initiate studies in a new but related area involving systemic lupus erythematosus. This condition represents an autoimmune disease in which the issue of reproductive risk remains unresolved. We feel that whole embryo cultures in conjunction with human sera analyses would be useful in defining the nature of the reproductive risk factors associated with this disease.
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