Proprotein Convertase 6: a Master Regulator for the Development of Endometrial Receptivity and Embryo Implantation

胚胎植入子宫(子宫)是人类发育的关键步骤，如果没有这一步骤，胚胎将只能发育到非常早期的囊胚期(受精后约8天)。对于成功的植入，子宫必须为接受胚胎做好准备；这一准备是至关重要的，因为准备不足的子宫会排斥胚胎。这种植入失败是导致早期妊娠丢失和女性不孕的主要原因；约30%的妊娠以自然流产告终。子宫是如何变得容易接受的还不是很清楚。我们最近的研究发现，原蛋白转换酶6(PC6)是一种重要的主开关，负责激活其他蛋白质，在子宫中受到严格调控，在其准备接受能力的过程中，对着床至关重要。这个项目将通过确定PC6控制的因素以及这种控制是如何工作的，来研究PC6如何在人类子宫中发挥作用，使其易于接受。我们将使用从人足月胎盘分离细胞的细胞培养模型。此外，由于缺乏可靠的生物标志物，没有办法容易地测试子宫是否接受。在这项研究中，我们将确定PC6(以及那些由PC6控制的分子)是否是子宫容受性的潜在生物标志物。这将通过检查子宫活检和从已证实有生育能力的志愿者和已证实的子宫内膜不孕症患者身上收集的子宫冲洗液来实现。这项研究将极大地提高我们对关键分子PC6在子宫中如何作用于植入的理解。这一结果将为子宫植入准备提供新的知识。这项研究对于开发急需的子宫容受性和不孕症的诊断和治疗工具具有相当大的意义。

Implantation of an embryo into the womb (uterus) is a key step for human development, without which the embryo will only be able to develop to a very early stage the blastocyst stage (about 8 days after fertilization). For successful implantation, the uterus has to prepare itself to be receptive; this preparation is crucial as an ill-prepared uterus will reject the embryo. Such implantation failure is a major cause of early pregnancy loss and female infertility; ~30% of pregnancies end in spontaneous abortion. How the uterus becomes receptive is not well understood. Our recent research has identified that proprotein convertase 6 (PC6), an important master switch responsible for activating other proteins, is tightly regulated in the uterus during its preparation for receptivity and critical for implantation. This project will examine how PC6 acts in the human uterus to make it receptive, by identifying the factors that PC6 controls and how this controlling works. We will use a cell culture model with cells isolated from human term placenta. In addition, there is no means of readily testing whether the uterus is receptive owing to the lack of reliable biomarkers. In this study we will determine whether PC6 (and those molecules controlled by PC6) are potential biomarkers for uterine receptivity. This will be achieved by examining uterine biopsies and uterine washings collected from proven fertile volunteers and patients of proven endometrial infertility. This study will greatly enhance our understanding of how a critical molecule, PC6, acts in the uterus for implantation. The results will provide new knowledge regarding uterine preparation for implantation. The study has considerable implication for developing much-needed diagnostic and therapeutic tools for uterine receptivity and infertility.