Molecular signaling in uterine receptivity to implantation

描述（由申请人提供）：人类生殖是复杂的，效率不高。超过30%的怀孕导致自然流产，大多数损失发生在着床时，由于子宫环境不充分。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具有植入能力的囊胚和接受子宫之间有效的双向相互作用。只有这种分子对话建立起来，囊胚才会植入。子宫从前受精期到受精期再到非受精期的潜在机制尚不清楚。我们推测肌段同源盒（Msh）家族的两个高度保守的基因（Msx1和Msx2）在子宫接受性和不接受着床中起关键作用。在我们提出的研究中，我们将验证这样的假设，即这些形态发生基因在发育过程中对上皮-间质相互作用至关重要，也在着床过程中发挥关键作用，通过非规范的Wnt信号通路，包括E-cadherin-2-catenin复合物的形成，改变上皮细胞的极性和完整性。为了验证我们的假设，我们将在老鼠身上进行两个特定的实验。第一个具体目标将检验假设，虽然Msx1是植入的主要关键因素，但Msx2在Msx1缺失时具有补偿作用。第二个具体目标将检验Msx1和/或Msx2通过影响上皮细胞极性和完整性直接植入的假设。本建议的总体目标是为了更好地了解直接子宫接受性和非接受性的机制，以提高女性的生育能力。我们将使用有条件基因删除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能力相关的机制信息，而由于伦理限制，这些信息无法在人类中进行。然而，我们将与临床科学家合作，确定我们在小鼠身上的发现的临床相关性。

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.