The Role of Progesterone Receptor in the Oviduct Epithelium for Pregnancy Establishment

项目摘要/摘要： 80%的妊娠丢失发生在妊娠的前三个月，然而，原因与输卵管畸形有关 输卵管(在其他物种中称为“输卵管”)通常是未知的。因为我们对这个问题缺乏全面的了解 输卵管内环境及其在调节早孕中的作用，很难提供诊断工具 用于输卵管起源的早期妊娠丢失。尽管已经做出努力来模拟输卵管环境 辅助生殖技术(ART)的成功率仍然很低。文献表明， 与输卵管上皮细胞共培养可提高受精率和胚胎质量 输卵管上皮细胞衬里与胚胎之间发生相互作用以支持胚胎 发展。在胚胎发育的第一天，孕酮(P4)的丢失会导致 胚胎发育和女性上皮细胞经典孕激素受体(PGR)的消融 生殖道(称为上皮Pgrd/d)导致不孕，部分原因是子宫植入缺陷。然而， 上皮细胞中的PGR对输卵管功能的需求尚未得到评估。我们建议 附植前胚胎发育过程中输卵管上皮PGR功能需求的研究 怀孕机构。使用上皮Pgrd/d小鼠模型，我们的初步研究已经证明 上皮PGR的表达是输卵管内正常植入前胚胎发育所必需的。我们进一步 目的确定这种发育缺陷的原因，并在缺乏胚胎死亡的情况下增加胚胎死亡。 上皮性PGR。初步数据显示PGR消融时炎症反应基因上调 这可能会导致不适合在输卵管内发育胚胎的环境。 这些目标的成功完成将提供对P4信号转导作用的更全面的理解 通过经典的PGR在输卵管上皮细胞中调节炎症反应和着床前 孕期发育可能有助于早期妊娠的诊断标志物 损失。目标1和目标2中提出的研究预计将分别在第1年和第2年完成。此外 对于这些拟议的目标，专业发展、科学写作、沟通和网络技能将 第一年和第二年的进展。开放实验室空间和生殖生物学中心 华盛顿州立大学将鼓励合作，并提供必要的资源、设备和 实现拟议目标的设施。

Project Summary/Abstract: 80% of pregnancy loss occurs during the first trimester, however, the cause associated with defective Fallopian tubes (termed “oviduct” in other species) is often unknown. Because we lack a complete understanding of the environment within the oviduct and its role in regulating early pregnancy, it is difficult to provide diagnostic tools for oviductal origin of early pregnancy loss. Although efforts have been made to mimic the oviductal environment for Assisted Reproductive Technology (ART), the success rate still remains low. The literature has shown that co-culture with oviduct epithelial cells improves fertilization rate and embryo quality suggesting that important interactions occur between the epithelial cell lining of the oviduct and the embryo to support embryonic development. Loss of progesterone (P4) during the first day of embryo development leads to a disruption in embryo development and ablation of classical progesterone receptor (Pgr) in the epithelial cells of the female reproductive tract (called epithelial Pgrd/d) causes infertility, partly due to a uterine implantation defect. However, the requirement of PGR in the epithelial cells on oviductal function has not yet been evaluated. We propose to study the functional requirement of epithelial PGR in the oviduct during preimplantation embryo development for pregnancy establishment. Using the epithelial Pgrd/d mouse model, our pilot studies have demonstrated that epithelial PGR expression is required for normal preimplantation embryo development in the oviduct. We further aim to determine the cause of this developmental defect and increase in embryo death in the absence of epithelial PGR. Preliminary data shows an upregulation of inflammatory response genes when Pgr is ablated from the epithelium, which may lead to an environment not suitable for developing embryos in the oviduct. Successful completion of these aims will provide a more comprehensive understanding of the role of P4 signaling through classical PGR in the oviduct epithelial cells to regulate the inflammatory response and preimplantation development during pregnancy establishment that may contribute to diagnostic markers for early pregnancy loss. Research proposed in Aims 1 and 2 is anticipated to be completed in Years 1 and 2, respectively. In addition to these proposed aims, professional development, science writing, communication and networking skills will progress during Year 1 and Year 2. The open laboratory space and Center for Reproductive Biology at Washington State University will encourage collaboration and provide the necessary resources, equipment, and facilities to carry out the proposed aims.