Modulation of the Receptive Endometrium and Decidualization by Notch

项目摘要 蜕膜化的定义是子宫内膜间质成纤维细胞转化为一种特殊的分泌物。 蜕膜细胞。这种转变对于胚胎植入和胎盘发育是必不可少的。在此之前 蜕膜化的开始，子宫内膜必须过渡到接受状态，植入需要 胚胎和接受子宫之间的精确同步。在灵长类动物中，蜕膜化需要 孕酮(P)和cAMP水平升高。尽管许多细胞事件在过程中发生 蜕膜化作用已经被描述，确切的基因以及细胞和分子通路 对这一过程的调控还有待阐明。我们的研究为NOTCH1在 开始蜕膜化。NOTCH1是细胞命运的一个高度保守的仲裁者，它调节着 是蜕膜化所必需的。在蜕膜化过程中，NOTCH1与FOXO1相互作用，启动这一关键过程 NOTCH1信号通路的转录激活需要P.当Notch 在子宫内膜异位症的情况下，信号转导受到影响，间质细胞无法蜕膜。或者， 异位内膜中NOTCH1的过度表达可能参与了病变的发生发展。在这 应用：我们提出了三个具体目标来理解相关的细胞和分子机制 蜕膜化过程中NOTCH1信号转导及NOTCH1异常表达的影响 子宫内膜异位症相关病理。目标1，将重点研究NOTCH1和NOTCH1之间的关键相互作用 我们假设的Foxo1对于启动蜕膜化和NOTCH1的过程是至关重要的 抑制CREB介导的cAMP激活将基质细胞转化为完全分化的 蜕膜表型。在目标2中，我们将检验P在体内和体内调节NOTCH1裂解的假设 它对靶基因的核转位和转录激活至关重要。 NOTCH1的胞内结构域(N1ICD)。目的3，我们将检验NOTCH1过度表达的假设 PU1介导的PGR甲基化促进子宫内膜异位症的病理生理作用 DNMT3b的募集和诱导上皮细胞向间充质转化(EMT)。该目标还将使用 过度表达N1ICD的PRCre小鼠模型。这些研究我们将进一步阐明NOTCH1- 蜕膜化的关键调控途径及其表达变化的意义 导致子宫内膜异位症伴发不孕症。这些研究具有翻译意义，因为如果 蜕膜化的启动或进展受到影响，结果是早期妊娠失败。

Project Summary Decidualization is defined as the transformation of endometrial stromal fibroblasts into a specialized secretory decidual cell. This transformation is essential for embryo implantation and placental development. Prior to the onset of decidualization, the endometrium must transition into a receptive state and implantation requires a precise synchronization between the embryo and the receptive uterus. In primates decidualization requires both progesterone (P) and increasing levels of cAMP. Although many of the cellular events that occur during decidualization have been described, the precise genes as well as the cellular and molecular pathways that regulate this process remain to be elucidated. Our studies have provided an essential role for NOTCH1 in the initiation of the decidualization. NOTCH1 is a highly conserved arbiter of cell fate and regulates processes that are required for decidualization. During decidualization, NOTCH1 interacts with FOXO1 to initiate this critical process and that the transcriptional activation of NOTCH1 signaling pathways requires P. When Notch signaling is compromised in the context of endometriosis, stromal cells are unable to decidualize. Alternatively, the overexpression of NOTCH1 in the ectopic endometrium may contribute to lesion development. In this application we propose three specific aims to understand the cellular and molecular mechanisms associated with NOTCH1 signaling during decidualization and the impact of aberrant NOTCH1 expression in endometriosis associated pathologies. Aim 1, will focus studying the critical interactions between NOTCH1 and FOXO1 which we hypothesize are critical for initiating decidualization and the process by which NOTCH1 is suppressed to allow CREB-mediated cAMP- activation to transform the stromal cells into the fully differentiated decidual phenotype. In Aim 2, we will test the hypothesis that P regulates NOTCH1 cleavage in vivo and in vitro which is critical for the nuclear translocation and transcriptional activation of target genes by the intracellular domain of NOTCH1 (N1ICD). Aim 3, we will test the hypothesis that overexpression of NOTCH1 contributes to the pathophysiology of endometriosis by promoting methylation of Pgr via PU.1 mediated recruitment of DNMT3b and inducing epithelial to mesenchymal transition (EMT). This aim will also use a PRCre mouse model that overexpresses N1ICD. These studies we will further elucidate the NOTCH1- regulated pathways that are critical for decidualization and the implications of its altered expression in contributing to endometriosis associated infertility. These studies have translational significance because if the initiation or progression of decidualization is compromised the result is early pregnancy failure.