Molecular signaling in uterine receptivity to implantation

子宫植入容受性的分子信号传导

• 批准号: 8338882
• 负责人: Sudhansu K Dey
• 金额: $ 32.51万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8338882
• 关键词: Address; Adherence; Adhesions; Animal Model; Birth; Blastocyst Transfer; Cell Polarity; Clinical; Collaborations; Complex; Conceptions; Contraceptive Agents; 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）：人类繁殖很复杂，效率不是很高。超过30％的概念导致自发流产，由于子宫环境不足，大多数损失发生在植入时间左右。不必要的怀孕丧失是一个主要的心理，经济和临床问题。在胎盘哺乳动物中植入的一种先决条件是植入合理的胚泡和接受子宫之间的有效双向相互作用。仅当建立这种分子对话时，胚泡才会植入。子宫从受障碍到接受相传为非受体相的基本机制仍然未知。我们假设肌肉段同源物（MSH）家族的两个高度保守的基因（MSX1和MSX2）在子宫接受性和对植入的非受体症中具有关键作用。在拟议的研究中，我们将检验以下假设：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，也通过通过非典型的Wnt信号传导涉及E-Cadherin-2-catenin-2-catenin综合型形成，通过改变上皮细胞的极性和完整性，在植入中起着至关重要的作用。为了检验我们的假设，我们将在小鼠中追求两个具体目标。第一个具体目的将检验以下假设：尽管MSX1是植入的主要关键因素，但如果缺少MSX1，MSX2具有补偿性作用。第二个特定目标将通过影响上皮细胞极性和完整性来检验MSX1和/或MSX2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接受性和非受伤性的机制，以改善女性生育能力。我们将使用有条件的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械信息，而这些信息由于道德限制而无法在人类中追求。但是，我们将与临床医生合作，以确定小鼠发现的临床相关性。