The uterus is a remarkable example of an adult tissue that undergoes cyclic differentiation involving multiple intercellular interactions. One dramatic uterine process is embryo implantation and the phenomenon of maternal immune tolerance to the embryo. Another is the decidual cell response, involving morphological and biochemical differentiation of the uterine stroma usually at the site of embryo implantation. It has long been observed that the above processes are tightly regulated by the ster- oid hormones, estrogen (E) and progesterone (P). More recently a number of studies have demonstrated marked changes in the cell type-specific expression of growth factors (GFs) in the uterus during implantation and decidualization. In spite of the tremendous biological importance of steroid hormone/GF interplay, our understanding of these events is limit- ed. Although it is clear that the uterine expression of certain GFs or their receptors changes in response to steroid hormones, the biochemical consequences of these changes are unknown. Three GF systems that deserve particular attention in this regard are those for EGF/TGF-alpha, IGF-1 and CSF-1. TGF-beta also is interesting from a number of standpoints including its effects on extracellular matrix (ECM) expression, immunosuppression and its production by blastocysts and macrophages. In addition, other GFs produced by uterine epithelial cells (UEC), stromal cells (USC) or macro- phages may be sources of and targets for intercellular signals. UEC and USC display several biochemical responses to steroid hormones that may be GF-mediated. These responses include altered patterns of glycoprotein and ECM expression, intermediate filament protein (desmin) expression and prostaglandin (PG) secretion. In this proposal, we will use a recently- developed cell-cell recombination system to determine if particular GFs or other secretory products of UEC or USC modulate these particular bio- chemical responses in vitro. our goals are: 1) to define the direct effects of EGF/TGF-alpha, IGF-1, CSF-1 and TGF-beta on the aforementioned bio- chemical responses of UEC and USC and 2) to determine if GFs secreted by UEC, USC or macrophages in vitro modulate these responses.
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