The overall goal is to determine how the gonadal steroid hormone, estrogen, modulates peritoneal adhesion formation. The hypothesis is that estrogen alters connective tissue deposition and the murine model of peritoneal adhesion formation by exerting direct effects on the expression of JE, the murine homologue of the human monocyte chemoattractant protein-1 (MCP-1) in macrophages and fixed mesenchymal cells (such as fibroblast and mesothelial cells). Previous work demonstrated that ovariectomized mice given estradiol replacement had 63 percent less abdominal wall connective tissue than talc treated ovariectomized animals given placebo. The studies described involve a multifaceted analysis of the role of estrogen in the production of peritoneal adhesion formation by: a) determining whether the inhibitory effects of 17beta-estradiol in the deposition of connective tissue is a direct effect of steroid hormone or indirectly mediated by other hormones and, b) identifying possible mechanisms by which 17beta-estradiol mediated suppression of JE mRNA expression could occur including examining secondary messenger systems pathways which lead to JE mRNA expression and defining genomic elements including estrogen response elements in the flanking sequences of the JE gene. These studies will expand our knowledge of the effects of estrogen on wound healing and tissue remodeling and lead to development of therapeutic regiments to treat or lessen the severity of disorders resulting from excessive connective tissue production.
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