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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD043381-03
Application #
6897268
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Yoshinaga, Koji
Project Start
2003-07-07
Project End
2008-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
3
Fiscal Year
2005
Total Cost
$309,825
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Das, Amrita; Li, Quanxi; Laws, Mary J et al. (2012) Estrogen-induced expression of Fos-related antigen 1 (FRA-1) regulates uterine stromal differentiation and remodeling. J Biol Chem 287:19622-30
Ramathal, Cyril Y; Bagchi, Indrani C; Taylor, Robert N et al. (2010) Endometrial decidualization: of mice and men. Semin Reprod Med 28:17-26
Das, Amrita; Mantena, Srinivasa Raju; Kannan, Athilakshmi et al. (2009) De novo synthesis of estrogen in pregnant uterus is critical for stromal decidualization and angiogenesis. Proc Natl Acad Sci U S A 106:12542-7
Laws, Mary J; Taylor, Robert N; Sidell, Neil et al. (2008) Gap junction communication between uterine stromal cells plays a critical role in pregnancy-associated neovascularization and embryo survival. Development 135:2659-68
Li, Quanxi; Kannan, Athilakshmi; Wang, Wei et al. (2007) Bone morphogenetic protein 2 functions via a conserved signaling pathway involving Wnt4 to regulate uterine decidualization in the mouse and the human. J Biol Chem 282:31725-32
Bagchi, Milan K; Mantena, Srinivasa R; Kannan, Athilakshmi et al. (2006) Control of uterine cell proliferation and differentiation by C/EBPbeta: functional implications for establishment of early pregnancy. Cell Cycle 5:922-5
Mantena, Srinivasa Raju; Kannan, Athilakshmi; Cheon, Yong-Pil et al. (2006) C/EBPbeta is a critical mediator of steroid hormone-regulated cell proliferation and differentiation in the uterine epithelium and stroma. Proc Natl Acad Sci U S A 103:1870-5
Li, Quanxi; Bagchi, Milan K; Bagchi, Indrani C (2006) Identification of a signaling pathway involving progesterone receptor, calcitonin, and tissue tranglutaminase in Ishikawa endometrial cells. Endocrinology 147:2147-54
Li, Quanxi; Cheon, Yong-Pil; Kannan, Athilaxmi et al. (2004) A novel pathway involving progesterone receptor, 12/15-lipoxygenase-derived eicosanoids, and peroxisome proliferator-activated receptor gamma regulates implantation in mice. J Biol Chem 279:11570-81
Chen, Dahu; Xu, Xueping; Cheon, Yong-Pil et al. (2004) Estrogen induces expression of secretory leukocyte protease inhibitor in rat uterus. Biol Reprod 71:508-14

Showing the most recent 10 out of 13 publications