The utero-placental unit produces many hormones which are believed to coordinate the successful pregnancy. In humans as well as ruminants, these include the evolutionary relatives of growth hormone and prolactin, placental lactogens (PL). By analogy to the pituitary hormones, the related placental hormones may play a role in a variety of processes in fetal development end maternal adaptations to pregnancy. Our long term goal is to understand the function of these related placental hormones in pregnancy, their mode of action, and basis for tissue end hormone specificity. Recently, three receptors for this hormone family have been described in the uterus. These placental hormones, including placental lactogen, are obvious local ligands. In order to study the actions of placental lactogen on the uterus, and study mediation of the hormonal signal, we have developed methods for primary culture of homologous uterine cells. The expression of hormone-specific receptors and the ability to respond to hormonal stimuli are characteristics of this model which offer an unique opportunity to dissect the complexities of maternal-fetal interactions. In these studies, we will focus our attention on modulation by bPL of the level of transcripts for stromelysin. We will describe the stromelysin response to bPL in epithelial cells with respect to time, concentration, site of bPL action on expression of this gene, and the receptors mediating this response. We will evaluate the role of other cytokines and growth factors in regulation of stromelysin expression in uterine cells, and their interactions with PL. In order to investigate bPL stimulation of transcription, we will identify cis-acting sequences in the stromelysin promoter by mutational analysis and gel shift essays. Finally, we will examine the effect of bPL on known signal transduction pathways by examining tyrosine phosphorylation and MAP kinase activities. These studies will aid in our understanding of the function of PL and related hormones in the uterus during pregnancy, increase our knowledge of signal transduction of this little-understood family of receptors, and integrate the GH/PRL gene family and their receptors into the cytokine network.
