Molecular signaling in uterine receptivity to implantation

描述(申请人提供)：人类繁衍繁衍复杂，效率不高。超过30%的受孕会导致自然流产，其中大多数流产发生在植入前后，原因是子宫环境不佳。意外妊娠丢失是一个主要的心理、经济和临床问题。在胎盘哺乳动物中植入的一个先决条件是能够着床的胚泡和接受子宫之间的有效双向相互作用。只有当这种分子对话建立起来时，胚泡才会被植入。子宫从前接受期到接受期再到非接受期的潜在机制尚不清楚。我们推测肌肉片段同源框(MSH)家族的两个高度保守的基因(Msx1和Msx2)在子宫对着床的接受性和非接受性中起关键作用。在这项拟议的研究中，我们将检验一种假设，即这些在发育过程中对上皮-间充质相互作用至关重要的形态发生基因，也通过涉及E-钙粘蛋白-2-连环蛋白复合体形成的非规范Wnt信号改变上皮细胞的极性和完整性，在着床过程中发挥关键作用。为了验证我们的假设，我们将在老鼠身上追求两个特定的目标。第一个具体目标将检验这样的假设，即虽然Msx1是植入的主要关键因素，但如果Msx1缺失，MSX2具有补偿作用。第二个特定目标将检验Msx1和/或MSX2通过影响上皮细胞的极性和完整性而直接植入的假设。这项建议的总体目标是为了更好地了解指导子宫容受性和非容受性的机制，目的是提高女性的生育力。我们将使用有条件的基因缺失小鼠模型来解决这些事件的分子基础，因为这些模型提供了与女性生育相关的机械信息，而由于伦理限制，人类无法追求这些信息。然而，我们将与临床科学家合作，确定我们在小鼠身上发现的临床相关性。

DESCRIPTION (provided by applicant): Human reproduction is complex and not very efficient. More than 30% of conceptions result in spontaneous abortion with most losses occurring around the time of implantation due to an inadequate uterine milieu. Unwanted pregnancy loss is a major psychological, economical and clinical problem. One prerequisite for implantation in placental mammals is an effective two-way interaction between an implantation- competent blastocyst and the receptive uterus. The blastocyst will implant only when this molecular dialogue is established. The underlying mechanism by which a uterus transits from the pre-receptive to the receptive to the non-receptive phase remains unknown. We hypothesize that two highly conserved genes (Msx1 and Msx2) of the muscle segment homeobox (Msh) family have key roles in uterine receptivity and non-receptivity to implantation. In the proposed study, we will test the hypothesis that these morphogenetic genes, critical for epithelial-mesenchymal interactions during development, also play crucial roles in implantation by altering the epithelial cell polarity and integrity via a non- canonical Wnt signaling involving E-cadherin-2-catenin complex formation. To test our hypothesis, we will pursue two specific aims in mice. The first specific aim will test the hypothesis that while Msx1 is a major critical factor in implantation, Msx2 has a compensatory role if Msx1 is missing. The second specific aim will test the hypothesis that Msx1 and/or Msx2 direct implantation by influencing the epithelial cell polarity and integrity. The overall goal of this proposal is to better understand the mechanisms that direct uterine receptivity and non-receptivity with the aim of improving female fertility. We will use conditionally gene-deleted mouse models to address the molecular basis of these events, since these models provide mechanistic information relevant to female fertility which cannot be pursued in humans due to ethical restrictions. However, we will collaborate with clinician scientists to determine clinical correlates of our findings in mice.