Molecular Analysis of Uterine Receptivity

描述(申请人提供)：子宫容受性，即子宫接受胚胎植入的能力，取决于卵巢类固醇信号，它协调子宫内膜上皮和间质之间的旁分泌串扰。卵巢类固醇孕酮P4通过其同源受体PGR(小鼠)起作用，在调节隔室串扰中起关键作用。在妊娠期间，PGR在胚胎附着之前的一段时间内在子宫上皮细胞中表达。在人类中，PGR信号的改变与子宫内膜疾病有关，如不孕症、子宫内膜异位症和子宫内膜癌。PGR过度刺激与体外受精-胚胎移植、IVF/ET后妊娠失败有关。这项建议的目的是研究PGR调节的分子机制，以及它们如何在调节子宫容受性和疾病方面发挥作用。利用染色质免疫沉淀结合全基因组测序、芯片序列分析，我们已经确定了PGR在小鼠基因组中的结合部位，并确定了转录因子Sox17是PGR的靶标和PGR在调节子宫容受性方面的潜在合作伙伴。这一假设认为，PGR和Sox17的细胞特异性和时间性相互作用对子宫容受性至关重要，Sox17和PGR表达的改变将损害子宫功能。这项建议将研究Sox17在调节小鼠子宫功能中的作用。然后，我们将研究Sox17在子宫内膜功能调节中的分子相互作用。最后，我们将测试计时的重要性 PGR调节小鼠子宫容受性的信号转导。完成本研究的目的将明确PR在子宫内膜功能调控中的作用，并确定PR与其他转录因子在调控子宫内膜基因表达和功能中的功能相互作用。这一建议也将决定PR在子宫中的重要性或表达的时间性。了解PR的表达变化如何扰乱子宫功能，对于了解子宫对内分泌治疗的反应至关重要。

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.