PROSTAGLANDIN SIGNALING IN FEMALE REPRODUCTION

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DESCRIPTION (Adapted from the applicant's description): Cyclooxygenase (COX)-derived PGs are implicated in many aspects of reproduction, including ovulation, implantation and parturition, yet limited information is available regarding the regulation of PG ligand-receptor signaling in the uterus. This application will provide the principal investigator (PI) with a balanced educational and research program to investigate mechanisms of PG signaling in the mouse under the mentorship of an established reproductive scientist. The proposal is supported by advisors with expertise in parturition and PG biology. Premature birth remains a perplexing clinical problem despite efforts to identify and treat the underlying causes of preterm labor. The applicant is examining parturition in the mouse to better understand the molecular basis of this process. Preliminary results show that: 1) distinct expression of COX-1 and COX-2 occurs in the term uterus; 2) estrogen and progesterone receptors co-localize to the specific sites of COX-1 and COX-2 expression, respectively; 3) COX-2-derived PGs do not compensate for parturition failure in COX-1-/- mice, although exogenous PGs are effective; and 4) fetal PGs rescue parturition failure in COX-1 -/- recipient mice carrying wild-type embryos resulting from embryo transfer. Collectively, these results suggest that multiple aspects of parturition converge on the PG signaling pathway. The effects of ovarian steroids and the receptors that transduce PG signals during parturition are poorly defined. Thus, a model for parturition that encompasses these ligand and receptor relationships is needed. The objective of this application is to identify the cellular source of PGs and their receptors, examine the influence of ovarian steroids on their expression, and determine the contribution of fetal PGs to parturition in the mouse. The central hypothesis is that estrogen and progesterone exert significant effects on parturition by altering the levels of PG ligands or receptors, and that uterine contractility and cervical maturation during term and preterm labor are mediated by the differential actions of distinct PG receptors. The applicant will use genetic and pharmacologic approaches to: 1) examine the source and steroid regulation of PG synthesis during term or preterm labor; 2) determine the sites of PG actions during term or preterm labor; 3) quantify the contribution of fetal and placental-derived PGs to term and preterm labor; and 4) determine whether preterm labor occurs in PG-deficient mice and whether this is regulated by different pathways than in wild-type mice. The study will use COX-1-/- and cPLA2-/- mice, selective COX inhibitors, and an established method for induction of preterm labor. The results of these experiments will enhance the understanding of maternal-fetal PG signaling, and are likely to provide new insights into premature or dysfunctional labor in women.