Uterine receptivity, the ability of the uterus to accept embryo implantation, is dependent upon ovarian steroid signaling which coordinates the paracrine crosstalk between the epithelial and stromal compartments of the endometrium. The ovarian steroid Progesterone, P4, acting through its cognate receptor, Pgr (mouse), is critical in the regulation of the compartmental crosstalk. During pregnancy, Pgr is expressed in the uterine epithelial for a finite period prior to embryo attachment. In humans, alteration in the PGR signaling is associated with endometrial diseases, such as infertility, endometriosis, and endometrial cancer. Hyperstimulation of PGR is associated with pregnancy failure after in vitro fertilization and embryo transfer, IVF/ET. The goal of this proposal is to investigate the molecular mechanisms regulated by Pgr and how they function in the regulation of uterine receptivity and disease. Utilizing Chromatin Immunoprecipitation combined with whole genome sequencing, ChIP-Seq, we have identified the binding sites of Pgr in the murine genome and have identified the transcription factor Sox17 as a Pgr target and potential partner of Pgr in the regulation of uterine receptivity. The hypothesis of this proposal is that cell specific and temporl interactions of Pgr and Sox17 are critical for uterine receptivity and alterations in the expressio of Sox17 and Pgr will impair uterine function. This proposal will investigate the role of Sox17 in the regulation of mouse uterine function. We will then investigate the molecular interactions of Sox17 in the regulation of endometrial function. Finally, we will test the importance of the timing of Pgr regulated signaling in mouse uterine receptivity. Completion of the aims of this proposal will define the role of PR in the regulation of endometrial function and determine the functional interactions of PR with other transcription factors in the regulation of endometrial gene expression and function. This proposal will also determine the importance or the temporal expression of PR in the uterus. Understanding how altered expression of PR disrupts uterine function is critical in understanding how the uterus response to endocrine therapy.

Public Health Relevance

Diseases of the uterus, such as infertility, endometriosis and endometrial cancer are a result of altered responses of the uterus to progesterone. The goal of this proposal is to investigate how the hormone progesterone, acting though its receptor regulates the ability of the uterus to support embryo implantation and control processes that prevent diseases, such as endometriosis and endometrial cancer.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
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Yoshinaga, Koji
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Baylor College of Medicine
Anatomy/Cell Biology
Schools of Medicine
United States
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Large, Michael J; Wetendorf, Margeaux; Lanz, Rainer B et al. (2014) The epidermal growth factor receptor critically regulates endometrial function during early pregnancy. PLoS Genet 10:e1004451
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Clementi, Caterina; Tripurani, Swamy K; Large, Michael J et al. (2013) Activin-like kinase 2 functions in peri-implantation uterine signaling in mice and humans. PLoS Genet 9:e1003863
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Wetendorf, Margeaux; Demayo, Francesco J (2012) The progesterone receptor regulates implantation, decidualization, and glandular development via a complex paracrine signaling network. Mol Cell Endocrinol 357:108-18
Afshar, Yalda; Jeong, Jae-Wook; Roqueiro, Damian et al. (2012) Notch1 mediates uterine stromal differentiation and is critical for complete decidualization in the mouse. FASEB J 26:282-94
Franco, Heather L; Rubel, Cory A; Large, Michael J et al. (2012) Epithelial progesterone receptor exhibits pleiotropic roles in uterine development and function. FASEB J 26:1218-27

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