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.

胚胎植入是妊娠成功的门户。胚泡和子宫对于植入至关重要。健康植入室（地穴）的形成至关重要正常胚胎植入；异常的隐窝会导致差异。平面细胞极性（PCP）是非经典WNT5A信号通路的经典下游目标。 vang的子宫缺失像蛋白质2（vangl2）一样，主要的PCP组件会严重脱轨，胚胎间距，胚胎间距，和义词化，最终损害了妊娠结局。我们发现隐窝始终源于植入植入之间直接交流的腺体胚泡和腺体。肝素结合EGF样生长因子（HB-EGF）专门表达如果转移到第4天，伪孕剂子宫，类似于正常妊娠的Evoke植入样变化。但是，这些反应没有发生在子宫中，缺少vangl2，这表明vangl2的相交带有HB-EGF信号传导。 HB-EGF通过EGF的受体家族（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。该建议将测试一本小说假设HB-EGF信号通过使ERBBS参与参与PCP信号传导与PCP信号转导植入。通过ERBBS 1-4工作的HB-EGF诱导酪氨酸磷酸化。我们的初步结果表明，vangl2与ERBB2和ERBB3的物理关联，这表明这些受体，如果被HB-EGF激活，则磷酸化vangl2。以下两个具体目标将使用小鼠模型在植入中PCP和HB-EGF信号传导之间的研究相互作用：具体目标1将检验以下假设：HB-EGF信号与VANGL2信号相交以直接合适的腺体 - 晶体组件的形成，用于植入之间的直接串扰胚泡和腺体。两种不同的信号通路的互锁涉及 ERBB受体家族成员的磷酸化，然后经磷酸化 vangl2。特定目标2将检验HB-EGF和VANGL2功能耦合的假设植入中的信号需要在子宫上皮中存在ERBB1，ERBB2和/或ERBB3 和/或基质。我们将使用PGR-CRE和LTF-使用ERBB1，ERBB2和/或ERBB3的条件删除 ICRE驱动器探索子宫中的Vangl2磷酸化状态，并将这些结果与怀孕表型。该项目的成功完成将揭示一个概念属性植入和怀孕生物学领域，生长因子信号通路与PCP相交在形成植入室（隐窝）中的信号传导，以获得妊娠成功。