Modulation of the Receptive Endometrium and Decidualization by Notch

项目摘要 蜕膜化是指子宫内膜间质成纤维细胞转化为分泌型的细胞， 蜕膜细胞这种转化对于胚胎着床和胎盘发育至关重要。之前 在蜕膜化开始时，子宫内膜必须转变为接受状态，植入需要一个 胚胎和子宫之间的精确同步。在灵长类动物中， 孕酮（P）和cAMP水平增加。尽管许多细胞活动发生在 已经描述了蜕膜化，精确的基因以及细胞和分子途径， 调节这一过程仍有待阐明。我们的研究提供了NOTCH 1在 开始蜕膜化。NOTCH 1是一种高度保守的细胞命运仲裁者， 是蜕膜化所必需的。在蜕膜化过程中，NOTCH 1与FOXO 1相互作用，启动了这一关键过程。 Notch 1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，信号传导受损，基质细胞不能蜕膜化。可选择地， 异位内膜中NOTCH 1的过度表达可能有助于病变的发展。在这 我们提出了三个具体的目标，以了解相关的细胞和分子机制， 在蜕膜化过程中与NOTCH 1信号传导的关系以及NOTCH 1表达异常对 子宫内膜异位症相关病理。目标1，将重点研究NOTCH 1和 我们假设FOXO 1对启动蜕膜化至关重要，而NOTCH 1是通过FOXO 1启动蜕膜化的。 抑制以允许CREB介导的cAMP激活将基质细胞转化为完全分化的细胞。 蜕膜表型在目的2中，我们将检验P在体内和体外调节NOTCH 1切割的假设。 这对核转位和靶基因的转录激活至关重要。 NOTCH 1胞内结构域（N1 ICD）。目标3，我们将检验NOTCH 1过表达的假设 通过PU.1介导的Pgr甲基化促进子宫内膜异位症的病理生理学 募集DNMT 3b和诱导上皮向间充质转化（EMT）。该目标还将使用 过表达N1 ICD的PRCre小鼠模型。这些研究将进一步阐明NOTCH 1- 对蜕膜化至关重要的调节途径及其在子宫内膜中表达改变的意义 导致子宫内膜异位症相关的不孕症。这些研究具有翻译意义，因为如果 蜕膜化的开始或进展受到损害，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.