Molecular signaling in uterine receptivity to implantation

子宫植入容受性的分子信号传导

基本信息

批准号：
10631145
负责人：
Sudhansu K Dey
金额：
$ 43.91万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-26 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10631145
关键词：
3-Dimensional Biology Cells Communication Coupling Decidual Cell Reactions Dimensions Dimerization EGF gene ERBB2 gene Embryo Epidermal Growth Factor Receptor Epithelium ErbB Receptor Family Protein Event Family Fertility Gland Growth Factor Homo Human Implant Molecular Morphogenesis Mus Organ Orphan Phenotype Phosphorylation Positioning Attribute Pregnancy Pregnancy Outcome Process Proteins Publishing Reaction Receptor Protein-Tyrosine Kinases Recombinants Reproductive Health Research Role Signal Pathway Signal Transduction Site Stromal Cells Testing Time Transfer Factor Tyrosine Tyrosine Phosphorylation Uterus Vagina Visualization Women&apos s Health blastocyst cell motility conditional mutant design dimer gain of function heparin-binding EGF-like growth factor implantation loss of function member mouse model mutant mouse model natural Blastocyst Implantation novel planar cell polarity receptor response subfertility success uterine receptivity

项目摘要

Embryo implantation is a gateway to pregnancy success. A crosstalk between the blastocyst and uterus is vital to implantation. Formation of a healthy implantation chamber (crypt) is critical for normal embryo implantation; an abnormal crypt results in subfertility. Planar cell polarity (PCP) is a classic downstream target of the non-canonical Wnt5a signaling pathway. Uterine deletion of Vang- like protein 2 (Vangl2), a major PCP component, severely derails crypt formation, embryo spacing, and decidualization, ultimately compromising pregnancy outcomes. We have found that crypts invariably originate with preexisting glands conferring direct communication between the implanting blastocyst and glands. Heparin-binding EGF-like growth factor (HB-EGF) is exclusively expressed in the crypt epithelium surrounding the blastocyst, and beads preloaded with HB-EGF, if transferred to day 4 pseudopregnant uteri, evoke implantation-like changes similar to normal pregnancy. However, these responses fail to occur in uteri missing Vangl2, suggesting an intersection of Vangl2 with HB-EGF signaling. HB-EGF executes its function via the EGF family of receptors (Erbbs 1-4) as homodimers or heterodimers and induces tyrosine phosphorylation. This proposal will test a novel hypothesis that HB-EGF signaling intersects with PCP signaling by engaging the ErbBs in implantation. HB-EGF working via ErbBs 1-4 induces tyrosine phosphorylation. Our preliminary results show a physical association of Vangl2 with ErbB2 and ErbB3, suggesting that these receptors, if activated by HB-EGF, transphosphorylate Vangl2. The following two specific aims will study interactions between PCP and HB-EGF signaling in implantation using mouse models: Specific aim 1 will test the hypothesis that HB-EGF signaling intersects with Vangl2 signaling to direct the formation of an appropriate glands-crypt assembly for direct cross-talk between the implanting blastocyst and the glands. This interlocking of two different signaling pathways involves phosphorylation of members of the ErbB family of receptors followed by transphosphorylation of Vangl2. Specific aim 2 will test the hypothesis that the functional coupling of HB-EGF and Vangl2 signaling in implantation requires the presence of ErbB1, ErbB2 and/or ErbB3 in the uterine epithelium and/or stroma. We will use conditional deletion of ErbB1, ErbB2 and/or ErbB3 using Pgr-Cre and Ltf- iCre drivers to explore the Vangl2 phosphorylation status in the uterus, and correlate these results with pregnancy phenotypes. Successful completion of this project will reveal a conceptual attribute to the field of implantation and pregnancy biology that a growth factor signaling pathway intersects with PCP signaling in forming implantation chambers (crypts) for pregnancy success.

胚胎植入是成功怀孕的一个途径。囊胚和囊胚之间的串扰子宫对于着床至关重要。健康的着床室（隐窝）的形成对于胚胎正常着床；隐窝异常会导致生育能力低下。平面电池极性 (PCP) 是非经典 Wnt5a 信号通路的经典下游靶点。 Vang-子宫切除术像蛋白质 2 (Vangl2) 一样，PCP 的主要成分会严重破坏隐窝形成、胚胎间距、和蜕膜化，最终影响妊娠结局。我们发现，地穴总是起源于预先存在的腺体，赋予植入体之间的直接沟通囊胚和腺体。肝素结合 EGF 样生长因子 (HB-EGF) 独家表达在囊胚周围的隐窝上皮中，并且如果转移则预载有 HB-EGF 的珠子到第 4 天，假孕子宫会引起类似于正常妊娠的着床样变化。然而，这些反应在缺少 Vangl2 的子宫中无法发生，这表明 Vangl2 存在交叉具有 HB-EGF 信号传导。 HB-EGF 通过 EGF 受体家族 (Erbbs 1-4) 执行其功能作为同二聚体或异二聚体并诱导酪氨酸磷酸化。该提案将测试一部小说假设 HB-EGF 信号通过 ErbB 与 PCP 信号相交叉植入。 HB-EGF 通过 ErbBs 1-4 起作用，诱导酪氨酸磷酸化。我们的初步结果显示 Vangl2 与 ErbB2 和 ErbB3 存在物理关联，表明这些受体如果被 HB-EGF 激活，会使 Vangl2 转磷酸化。以下两个具体目标将使用小鼠模型研究植入过程中 PCP 和 HB-EGF 信号传导之间的相互作用：具体目标 1 将检验 HB-EGF 信号传导与 Vangl2 信号传导交叉以指导这一假设形成适当的腺体-隐窝组件，用于植入之间的直接串扰囊胚和腺体。两种不同信号通路的连锁涉及 ErbB 受体家族成员的磷酸化，随后进行转磷酸化范格2.具体目标 2 将检验 HB-EGF 和 Vangl2 功能耦合的假设着床过程中的信号传导需要子宫上皮中存在 ErbB1、ErbB2 和/或 ErbB3 和/或基质。我们将使用 Pgr-Cre 和 Ltf- 有条件删除 ErbB1、ErbB2 和/或 ErbB3 iCre 驱动程序探索子宫中的 Vangl2 磷酸化状态，并将这些结果与妊娠表型。该项目的成功完成将揭示该项目的概念属性生长因子信号通路与 PCP 交叉的植入和妊娠生物学领域形成植入室（隐窝）以确保妊娠成功的信号。