ASPECTS OF BLASTOCYST IMPLANTATION

描述（由申请人提供）：哺乳动物生殖的一个先决条件是具有着床能力的囊胚和接受子宫之间有效的相互作用。只有这种分子对话建立起来，囊胚才会植入。本建议的目的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。我们将使用条件基因删除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。人类的繁殖很复杂，效率也不高。超过30%的怀孕导致自然流产，大多数损失发生在着床时，由于不适当的子宫环境。意外流产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。基于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，对植入至关重要。为了解决这些问题，我们将在小鼠中进行以下特定目的：(1)第一个特定目的将验证Msx1通过改变腔上皮细胞极性和上皮-间质相互作用在调节子宫着床敏感性的各个阶段起关键作用的假设；(2)第二个特异性目的将检验Msx1和LIF密切相互作用指导子宫各阶段敏感的假设；(3)第三个Specific Aim将验证子宫Msx1过表达导致着床失败，但将子宫准备延伸到着床的假设。我们对子宫Msx1和/或Lif的条件删除的初步结果具有很大的希望，并为产生子宫成为可接受性或不可接受性的潜在机制的分子和遗传信息创造了机会。这项研究具有临床意义，因为Msx1在人类子宫内膜的受精期（植入窗口期）下调。这模拟了小鼠在植入开始前Msx1下调的情况。利用小鼠模型的研究结果可能有助于开发提高女性生育能力的新策略。

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.