ASPECTS OF BLASTOCYST IMPLANTATION

描述(由申请人提供)：哺乳动物繁殖的一个先决条件是有能力着床的胚泡和接受子宫之间的有效相互作用。只有当这种分子对话建立起来时，胚泡才会被植入。这项建议的目的是为了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性信息。人类的繁殖是复杂的，而且效率不是很高。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，原因是子宫环境不合适。意外妊娠丢失给家庭带来心理和经济压力，是一个具有挑战性的临床问题。根据我们已发表的和初步的结果，我们假设同源盒-细胞因子-Wnt信号，包括Msx1，白血病抑制因子(LIF)和Wnt5a，对着床至关重要。为了解决这些问题，我们将在小鼠上追求以下特定目标：(1)第一个特定目标将检验这样的假设，即Msx1通过改变子宫腔上皮细胞的极性以及上皮-间充质的相互作用，在调节子宫植入的不同阶段发挥关键作用；(2)第二个特定目标将检验Msx1和LIF密切相互作用从而指导子宫不同阶段的敏感度的假说；以及(3)第三个特定目标将检验以下假说：过表达子宫Msx1会导致着床失败，但延长了子宫对着床的准备。我们有条件地删除子宫Msx1和/或Lif的初步结果具有很大的希望，并创造了一个机会之窗，以产生关于子宫变得接受或不接受的潜在机制的分子和遗传信息。这项研究具有临床意义，因为Msx1在人类子宫内膜的接受期(着床窗口)下调。这模拟了小鼠在开始着床之前Msx1下调的情况。这项利用老鼠模型进行的拟议研究的结果可能有助于开发新的策略来提高女性的生育力。

DESCRIPTION (provided by applicant): One prerequisite for mammalian reproduction is an effective reciprocal interaction between an implantation-competent blastocyst and the receptive uterus. The blastocyst will implant only when this molecular dialogue is established. The goal of this proposal is to better understand the mechanisms that direct uterine receptivity and nonreceptivity 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 fertility in women. 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 inappropriate uterine milieu. Unwanted pregnancy loss causes psychological and economical stress to families, and is a challenging clinical problem. Based on our published and preliminary results, we hypothesize that homeobox-cytokine-Wnt signaling, involving Msx1, leukemia inhibitory factor (LIF) and Wnt5a, is critical for implantation. To address these questions, we will pursue the following specific aims in mice: (1) The first Specific Aim will test the hypothesis that Msx1 plays key roles in regulating various phases of uterine sensitivity to implantation by altering the luminal epithelial cell polarity and epithelial- mesenchymal interactions; (2) The second Specific Aim will test the hypothesis that Msx1 and LIF closely interact to direct various phases of uterine sensitivity; and (3) The third Specific Aim will test the hypothesis that overexpression of uterine Msx1 results in implantation failure, but extends the uterine preparedness to implantation. Our preliminary results with conditional deletion of uterine Msx1 and/or deletion of Lif hold great promise and have created a window of opportunity to generate molecular and genetic information on potential mechanisms by which the uterus becomes receptive or nonreceptive. This research is clinically relevant because Msx1 is downregulated in the human endometrium during the receptive phase (window of implantation).This simulates the situation in mice in which Msx1 is downregulated just prior to the initiation of implantation. The results derived from the proposed study using mouse models may help developing novel strategies to improve fertility in women.