Molecular signaling in uterine receptivity to implantation

子宫植入容受性的分子信号传导

• 批准号: 8877242
• 负责人: Sudhansu K Dey
• 金额: $ 31.7万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2016-09-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8877242
• 关键词: Address; Adherence; Adhesions; Animal Model; Birth; Blastocyst Transfer; Cell Polarity; Clinical; Collaborations; Complex; Conceptions; Contraceptive Agents; Craniofacial Abnormalities; Cytoskeleton; Defect; Development; E-Cadherin; Endometrium; Epithelial; Epithelial Cells; Epithelium; Estrogens; Ethics; Event; Family; Family member; Female; Female infertility; Fertility; Figs - dietary; Food; Gene Deletion; Genes; Goals; Hair follicle structure; Homeobox; Homeobox Genes; Human; Implant; Injection of therapeutic agent; Letters; Liquid substance; Mammals; Mesenchymal; Modeling; Molecular; Mus; Muscle; Pattern; Phase; Play; Powder dose form; Pregnancy; Pregnancy Rate; Pregnancy loss; Readiness; Refractory; Relative (related person); Reproduction; Role; Scientist; Seizures; Signal Pathway; Signal Transduction; Spontaneous abortion; Testing; Time; Tooth structure; Unwanted pregnancy; Uterus; Wild Type Mouse; Woman; base; blastocyst; clinically relevant; craniofacial; failure Implantation; implantation; improved; mouse model; natural Blastocyst Implantation; novel; novel strategies; placental mammal; psychologic; research study; success; transcription factor; uterine receptivity

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.

描述（由申请人提供）：人类繁殖非常复杂且效率不高。超过 30% 的受孕会导致自然流产，其中大多数损失发生在植入期间，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。胎盘哺乳动物植入的先决条件之一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。只有当这种分子对话建立时，囊胚才会植入。子宫从预接受期过渡到接受期再到非接受期的基本机制仍然未知。我们假设肌节同源盒 (Msh) 家族的两个高度保守的基因 (Msx1 和 Msx2) 在子宫容受性和不容受性着床中发挥关键作用。在拟议的研究中，我们将测试以下假设：这些形态发生基因对于发育过程中的上皮-间质相互作用至关重要，并且通过涉及 E-钙粘蛋白的非经典 Wnt 信号传导改变上皮细胞极性和完整性，从而在植入中也发挥着至关重要的作用。 2-连环蛋白复合物的形成。为了检验我们的假设，我们将在小鼠身上追求两个特定目标。第一个具体目标将检验以下假设：虽然 Msx1 是着床的主要关键因素，但如果 Msx1 缺失，Msx2 则具有补偿作用。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来直接植入的假设。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实现。然而，我们将与临床科学家合作，以确定我们在小鼠身上的发现的临床相关性。