Molecular signaling in uterine receptivity to implantation

描述（由申请人提供）：人类生殖是复杂的，不是很有效。超过30%的受孕导致自然流产，大多数流产发生在着床前后，原因是子宫环境不足。意外流产是一个重大的心理、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有植入能力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时，胚泡才会植入。子宫从前接受期到接受期再到非接受期的根本机制尚不清楚。我们推测，两个高度保守的基因（Msx 1和Msx 2）的肌肉节段同源框（Msh）家庭在子宫容受性和非容受性植入的关键作用。在所提出的研究中，我们将检验以下假设：这些形态发生基因对发育期间的上皮-间充质相互作用至关重要，通过涉及E-钙粘蛋白-2-连环蛋白复合物形成的非经典Wnt信号传导改变上皮细胞极性和完整性，在植入中也发挥关键作用。为了验证我们的假设，我们将在小鼠中实现两个特定目标。第一个具体目标将检验以下假设：虽然Msx 1是着床的主要关键因素，但如果Msx 1缺失，Msx 2具有补偿作用。第二个具体目标将检验Msx 1和/或Msx 2通过影响上皮细胞极性和完整性来指导着床的假设。该提案的总体目标是更好地了解指导子宫容受性和非容受性的机制，以提高女性生育力。我们将使用条件性基因缺失的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力相关的机制信息，由于伦理限制，这些信息不能在人类中进行。然而，我们将与临床科学家合作，以确定我们在小鼠中发现的临床相关性。

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.