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

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.

总结 人类的繁殖是复杂的，而且效率相当低。超过30%的概念 导致自然流产，大多数流产发生在 置入这些意外怀孕的损失导致了严重的心理， 经济和临床冲突。子宫环境不足是其中一个原因 失败-为了更深入地探索成功怀孕的机制，我们认识到 有能力的胚泡和接受胚泡之间有效的双向相互作用 子宫是在包括人类在内胎盘哺乳动物中植入的先决条件。的 胚泡只有在这种分子对话建立时才会植入。通常情况下， 在小鼠中的植入发生在专门的植入室（隐窝）内， 腔上皮（LE）向子宫的反系膜（AM）侧外翻。 朝向AM形成均匀间隔的隐窝的潜在机制 北极仍然难以捉摸。我们最近在小鼠中的研究表明，受调控的Wnt 5a-ROR 信号传导对于植入和妊娠建立是至关重要的。我们建议， 信号传导是由平面细胞极性（PCP）通过接合PCP组件介导的 Vangl 2、Scribble、Celsr 1和Dvl 2。我们将检验以下假设： 与非经典Wnt 5a-ROR信号传导的协作指导隐窝形成， 置入目标1将测试主要的PCP信号成分是否在子宫中活跃 在植入的时候。目的2将研究子宫PCP活性是否 对于通过使用遗传小鼠模型进行植入的隐窝形成至关重要。我们 在子宫缺失Vangl 2（PCP中的核心组分）的小鼠中的初步结果 信号）显示有缺陷的植入和受损的妊娠结果。这些 结果创造了一个独特的机会之窗， 关于子宫环境变得 有助于胚泡在隐窝中归巢以进行着床和妊娠 建立。遗传小鼠模型提供了与以下相关的机制信息： 女性生育能力，这在人类身上是不可行的。极有可能 PCP信号在人类植入中起着重要作用，因为人类蛋白质组 atlas已经记录了Vangl 2、Vangl 1和Wnt 5a在人子宫中的表达。 因此，谨慎的做法是收集有关五氯苯酚的机械和遗传证据 需要在小鼠模型中植入，以更好地了解人类植入。