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

项目总结/文摘:

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.