Molecular Analysis of Uterine Receptivity

子宫容受性的分子分析

• 批准号: 9300931
• 负责人: JOHN P LYDON
• 金额: $ 32.89万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9300931
• 关键词: Ablation; Binding; Binding Sites; Biochemical; Biological Assay; Cells; ChIP-seq; Critical Pathways; Data; Development; Disease; Embryo Transfer; Endometrial; Endometrial Carcinoma; Endometrium; Ensure; Enterobacteria phage P1 Cre recombinase; Epithelial; Epithelium; Erinaceidae; Estrogens; Event; Failure; Female sterility; Fertilization in Vitro; Funding; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; Genome; Goals; Heart; Hematopoietic; Hormones; Human; Impairment; In Vitro; Infertility; Modeling; Molecular; Molecular Analysis; Mus; Mutate; Ovarian; Pathway interactions; Physiological; Physiology; Pregnancy; Process; Progesterone; Regulation; Role; SOX17 gene; Signal Transduction; Steroids; Testing; Transgenes; Uterine Diseases; Uterus; chromatin immunoprecipitation; endometriosis; gene function; gene induction; genome sequencing; hormone therapy; in vivo; mouse model; natural Blastocyst Implantation; paracrine; preimplantation; prevent; public health relevance; receptor; response; transcription factor; transgene expression; uterine receptivity; whole genome

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.

描述（由申请人提供）：子宫接受性，即子宫接受胚胎植入的能力，取决于卵巢类固醇信号传导，该信号传导协调子宫内膜的上皮区室和基质区室之间的旁分泌串扰。卵巢类固醇黄体酮 P4 通过其同源受体 Pgr（小鼠）发挥作用，对于区室串扰的调节至关重要。在怀孕期间，Pgr 在胚胎附着之前的一段有限时间内在子宫上皮中表达。在人类中，PGR 信号传导的改变与子宫内膜疾病有关，例如不孕症、子宫内膜异位症和子宫内膜癌。 PGR 的过度刺激与体外受精和胚胎移植、IVF/ET 后妊娠失败有关。该提案的目的是研究 Pgr 调节的分子机制以及它们如何在子宫容受性和疾病的调节中发挥作用。利用染色质免疫沉淀结合全基因组测序 ChIP-Seq，我们鉴定了小鼠基因组中 Pgr 的结合位点，并确定转录因子 Sox17 作为 Pgr 靶标和 Pgr 在子宫容受性调节中的潜在伙伴。该提议的假设是，Pgr 和 Sox17 的细胞特异性和时间相互作用对于子宫容受性至关重要，并且 Sox17 和 Pgr 表达的改变将损害子宫功能。该提案将研究 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，我们来测试一下时机的重要性 Pgr 调节小鼠子宫容受性的信号传导。完成本提案的目标将明确PR在子宫内膜功能调节中的作用，并确定PR与其他转录因子在子宫内膜基因表达和功能调节中的功能相互作用。该提案还将确定 PR 在子宫中的重要性或时间表达。了解 PR 表达的改变如何破坏子宫功能对于了解子宫对内分泌治疗的反应至关重要。