Epithelial-trophoblast interactions in human embryo implantation: role for interleukin 11 and leukemia inhibitory factor

不孕、自然流产和先兆子痫是主要的临床问题。女性不孕症通常是由于植入失败，许多IVF胚胎未能植入。胎盘的适当发育对妊娠结局至关重要，胎盘形成不足可导致自然流产。然而，如果妊娠继续，胎盘发育不良，母亲很可能发展为先兆子痫，随后对母亲和婴儿都产生重大不良后果。先兆子痫是低出生体重婴儿和产妇死亡的最常见原因。低出生体重，这通常是妊娠先兆子痫的结果，与以后生活中的疾病（包括高血压，糖尿病，冠心病和肥胖）有关。白细胞介素（IL）-11和白血病抑制因子（LIF）是已知对小鼠胚胎植入至关重要的极少数分子之一。它们在人类不孕症中的作用尚不清楚，尽管有证据表明LIF减少与女性着床失败有关。这些分子在灵长类动物子宫和胎盘中的分布表明，它们在准备子宫内膜以供着床和妇女胎盘发育方面具有重要作用。该项目将研究植入部位局部产生的IL-11和LIF如何影响人类子宫和胎盘的形成。目前还没有一种方法可以很容易地诊断妇女的子宫内膜不孕症或确定胎盘是否发育良好。这些研究将提供关于这两种分子的作用及其作为不孕症和与妊娠相关的主要疾病急需的诊断和治疗工具的靶点的潜在有用性的新的关键信息。采用这种新的检测方法将对母亲和儿童的健康产生终身的好处。

Infertility, spontaneous abortion and pre-eclampsia are major clinical problems. Female infertility is frequently due to implantation failure and many IVF embryos fail to implant. Appropriate development of the placenta is critical to the outcome of pregnancy and inadequate placentation can result in spontaneous abortion. However, if the pregnancy continues with a poorly developed placenta, the mother is likely to develop pre-eclampsia with subsequent major adverse outcomes for both mother and baby. Pre-clampsia is the most common cause of low birth weight infants and also of maternal death. Low birth weight, which is commonly an outcome of a pregnancy with pre-eclampsia, correlates with disorders later in life (including hypertension, diabetes, coronary heart disease and obesity). Interleukin (IL)-11 and leukemia inhibitory factor (LIF) are among very few molecules known to be critical for embryo implantation in the mouse. Their roles in human infertility are not well understood, although there is evidence that decreased LIF is associated with implantation failure in women. The distribution of these molecules within the uterus and placenta in primates suggests they have important roles in preparing the uterine lining for implantation and for development of a placenta in women. This project will examine how IL-11 and LIF that are locally produced at implantation sites affect the human uterus and the formation of the placenta. There is still no means of readily diagnosing endometrial infertility in women or of establishing whether the placenta is developing adequately. These studies will provide new critical information regarding the roles of these two molecules and their potential usefulness as targets for much- needed diagnostic and therapeutic tools for infertility and major diseases associated with pregnancy. Application of such new tests will produce lifelong benefits to the health of both the mother and child.