Molecular Analysis of Uterine Receptivity

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DESCRIPTION (provided by applicant): 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.