Molecular signaling in uterine receptivity to implantation

子宫植入容受性的分子信号传导

• 批准号: 9975008
• 负责人: Sudhansu K Dey
• 金额: $ 38.13万
• 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 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975008
• 关键词: Address; Adult; Atlases; Biological Assay; Biology; Birth; Blood Vessels; Cell Polarity; Cell Proliferation; Cell Shape; Cells; Characteristics; Clinical; Collaborations; Communication; Complex; Conceptions; Conflict (Psychology); Cytokine Signaling; Cytosol; Data; Decidual Cell; Decidual Cell Reactions; Development; Embryo; Embryonic Development; Endometrial; Environment; Epithelial; Epithelium; Event; Failure; Female; Fertility; Fishes; Genetic; Genetic Transcription; Growth; Growth Factor; Homing; Human; Implant; Knowledge; Ligand Binding; Ligands; LoxP-flanked allele; Mechanics; Mediating; Molecular; Molecular Genetics; Morphology; Movement; Mus; Nuclear Translocation; Organogenesis; Ovarian hormone; Pathway interactions; Pattern; Phenotype; Phosphorylation; Placentation; Play; Positioning Attribute; Pregnancy; Pregnancy Outcome; Pregnancy Rate; Pregnancy loss; Process; Proteome; Records; Reproduction; Research; Role; Science; Side; Signal Transduction; Signaling Molecule; Site; Spontaneous abortion; Sterility; Stromal Cells; System; TCF Transcription Factor; Testing; Time; Unwanted pregnancy; Uterus; Vagina; Vascular Permeabilities; WNT Signaling Pathway; Woman; Work; beta catenin; blastocyst; cell motility; dosage; failure Implantation; female fertility; fly; genetic information; implantation; improved; morphogens; mouse model; novel strategies; placental mammal; planar cell polarity; psychologic; receptor; transcription factor; uterine receptivity; Address; Adult; Atlases; Biological Assay; Biology; Birth; Blood Vessels; Cell Polarity; Cell Proliferation; Cell Shape; Cells; Characteristics; Clinical; Collaborations; Communication; Complex; Conceptions; Conflict (Psychology); Cytokine Signaling; Cytosol; Data; Decidual Cell; Decidual Cell Reactions; Development; Embryo; Embryonic Development; Endometrial; Environment; Epithelial; Epithelium; Event; Failure; Female; Fertility; Fishes; Genetic; Genetic Transcription; Growth; Growth Factor; Homing; Human; Implant; Knowledge; Ligand Binding; Ligands; LoxP-flanked allele; Mechanics; Mediating; Molecular; Molecular Genetics; Morphology; Movement; Mus; Nuclear Translocation; Organogenesis; Ovarian hormone; Pathway interactions; Pattern; Phenotype; Phosphorylation; Placentation; Play; Positioning Attribute; Pregnancy; Pregnancy Outcome; Pregnancy Rate; Pregnancy loss; Process; Proteome; Records; Reproduction; Research; Role; Science; Side; Signal Transduction; Signaling Molecule; Site; Spontaneous abortion; Sterility; Stromal Cells; System; TCF Transcription Factor; Testing; Time; Unwanted pregnancy; Uterus; Vagina; Vascular Permeabilities; WNT Signaling Pathway; Woman; Work; beta catenin; blastocyst; cell motility; dosage; failure Implantation; female fertility; fly; genetic information; implantation; improved; morphogens; mouse model; novel strategies; placental mammal; planar cell polarity; psychologic; receptor; transcription factor; uterine receptivity

Summary Human reproduction is complex and fairly inefficient. More than 30% of conceptions result in spontaneous abortion with most losses occurring around the time of implantation. These unwanted pregnancy losses contribute to major psychological, economical, and clinical conflicts. Inadequate uterine milieu is one cause for this failure—to explore deeper into the mechanics of successful pregnancy, we recognize that effective two-way interactions between a competent blastocyst and the receptive uterus are a prerequisite for implantation in placental mammals including humans. The blastocyst will implant only when this molecular dialogue is established. Normally, implantation in mice occurs within a specialized implantation chamber (crypt) formed by luminal epithelial (LE) evaginations towards the antimesometrial (AM) side of the uterus. The underlying mechanism by which evenly spaced crypts are formed towards the AM pole remains elusive. Our recent work in mice shows that regulated Wnt5a-ROR signaling is critical to implantation and pregnancy establishment. We propose that this signaling is mediated by planar cell polarity (PCP) by engaging PCP components Vangl2, Scribble, Celsr1 and Dvl2. We will test the hypothesis that PCP activity in collaboration with non-canonical Wnt5a-ROR signaling directs crypt formation and implantation. Aim 1 will test if major PCP signaling constituents are active in the uterus around the time of implantation. Aim 2 will investigate whether uterine PCP activity is critical for crypt formation for implantation through the use of genetic mouse models. Our preliminary results in mice with uterine deletion of Vangl2 (a core component in PCP signaling) show defective implantation and compromised pregnancy outcomes. These results have created a unique window of opportunity to generate molecular and genetic information on a potential mechanism by which the uterine environment becomes conducive to blastocyst homing in the crypt for implantation and pregnancy establishment. The genetic mouse models provide mechanistic information relevant to female fertility which is not feasible to perform in humans. There is a strong possibility that PCP signaling plays a major role in human implantation, since the human proteome atlas has documented the expression of Vangl2, Vangl1 and Wnt5a in the human uterus. Thus, it is prudent to gather mechanistic and genetic evidence regarding PCP’s requirement in implantation in mouse models to better understand human implantation.

概括 人类的繁殖是复杂且相当低效率的。超过30％的概念 导致赞助流产，大多数损失发生在 植入。这些不必要的怀孕损失导致重大心理， 经济和临床冲突。子宫环境不足是这样做的原因之一 失败 - 深入探索成功怀孕的机制，我们认识到 胜任的胚泡和相关的有效的双向相互作用 子宫是在包括人类在内的斑点哺乳动物中植入的先决条件。这 仅当建立这种分子对话时，胚泡才会植入。通常情况下， 在小鼠中植入发生在由专门的植入室（隐窝）中 向子宫的抗符号（AM）侧的腔上皮（LE）逃避。 均匀间隔的加密蛋白向AM形成均匀间隔的加密蛋白的基本机制 杆仍然难以捉摸。我们最近在老鼠的工作表明WNT5A-ROR调节 信号对于植入和妊娠建立至关重要。我们提出这一点 信号传导是由平面细胞极性（PCP）通过参与PCP组件介导的 vangl2，cribble，celsr1和dvl2。我们将检验以下假设 与非典型Wnt5a-Ror信号的合作指导加密形成和 植入。 AIM 1将测试主要的PCP信号是否构成子宫中的活性 大约在植入时期。 AIM 2将研究子宫PCP活动是否是 通过使用遗传小鼠模型的植入植入至关重要。我们的 vangl2的子宫缺失的小鼠（PCP中的核心成分）的初步结果 信号传导）表现出缺陷的植入和受损的妊娠结局。这些 结果创造了一个独特的机会窗口来产生分子和遗传 有关子宫环境变为潜在机制的信息 在地下室中的胚泡归巢的导电植入和怀孕 建立。遗传鼠标模型提供了与 在人类中表现不可行的女性生育能力。有很大的可能性 PCP信号传导在人植入中起主要作用，因为人类蛋白质组 阿特拉斯（Atlas）记录了人子宫中vangl2，vangl1和wnt5a的表达。 那是谨慎地收集有关PCP的机械和遗传证据 在植入中的要求，在小鼠模型中可以更好地了解人植入。