The steroid hormone progesterone (P) profoundly influences the function of the uterus during establishment and maintenance of pregnancy. The cellular actions of P are mediated through intracellular progesterone receptor (PR) isoforms, PR-A and PR-B, which are well-known transcription factors. It is postulated that hormone-occupied PR triggers the expression of specific gene networks in different cell types within the uterus and the products of these genes mediate the hormonal effects. The long-term goal of this proposal is to identify and functionally characterize the PR-regulated pathways, which are critical mediators of P response within the uterus during early pregnancy.
The specific aims of this study are to: 1. Analyze PR isoform-specific regulation and expression of DNA microarray-derived genes in the preimplantation mouse uterus. Oligonucleotide microarrays were utilized to identify several genes whose expression is markedly down regulated in pregnant uterus at the time of implantation in response to a PR antagonist. The PR isoform-specific gene knock-out (KO) mouse models, PRAKO and PRBKO, will be employed to identify the genes that are potentially important for implantation. The spatio-temporal expression of these genes in the pregnant uterus will be analyzed. 2. Determine the functional roles of microarray-derived genes in the preimplantation uterus. Using a newly developed methodology, antisense oligodeoxynucleotides directed against mRNA transcripts of selected candidate genes will be administered into the preimplantation uterus to block specific gene expression during implantation. The functional effects of this intervention will be determined. In preliminary studies, antisense ODN-induced blockade of the expression of Irgl in the surface epithelium results in a severe impairment of implantation. The molecular target(s) of Irgl in the pregnant uterus will be identified by yeast two-hybrid approach. 3. Investigate the functional role of the PR-regulated protease inhibitor p12 in the decidual uterus, p12 is a serine protease inhibitor induced by P during trophoblast invasion and decidualization. The target protease(s) of p12 in the pregnant uterus will be identified by in vitro protein interaction methods and proteomics. Additionally, a p12 KO mouse will be developed and analyzed for potential reproductive defects. The proposed study will help us to identify molecules that are critical mediators of P regulation of embryo-uterine interactions during early pregnancy.
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