Ophan Nuclear Receptor COUPTF-II in Endometrial Biology

描述(由申请人提供)：本提案的总体目标是确定子宫准备以支持妊娠的基本分子机制，特别是孤儿核受体转录因子COUP-TFII在这一过程中的参与。利用孕激素受体敲除小鼠PRKO结合DNA微阵列技术，我们已经确定印度刺猬，IHH，形态发生途径是对孕酮反应最早的途径之一。IHH途径的下游靶点之一是孤儿核受体转录因子COUP-TFII。在小鼠中，COUP-TFII的表达是在胚胎接受窗口之前在子宫内膜上皮下间质中启动的 植入和是否在子宫内膜蜕膜转化过程中妊娠 间质细胞。从功能上讲，COUP-TFII是调节发育的关键因素。去除COUP-TFII可导致小鼠早期胚胎死亡。去除COUP-TFII杂合子的小鼠处于亚生育状态，部分原因是子宫支持着床的能力受损。在人类中，子宫内膜活检组织的DNA微阵列分析表明，与小鼠类似，COUP-TFII在人类子宫中的表达在着床期增加。在子宫内膜异位症组织中也观察到了COUPTF II的表达，并被认为在调节这种疾病组织的激素产生和生长方面起到了保护作用。这些实验室和临床观察表明，COUP-TFII在正常子宫功能和调节疾病状态下的子宫生物学方面发挥着重要作用。鉴于COUP-TFII在小鼠子宫生物学中扮演的关键角色，以及它在关键时刻在人类子宫内膜中的表达，该提案将把这些实验室发现转化为研究COUP-TFII在怀孕期间和病理状态下对人类子宫的调节和作用。这将通过以下步骤完成：1.确定COUP-TFII在人子宫内膜中的阶段和细胞特异性模式：2.确定人子宫内膜间质细胞COUP-TFII表达的旁分泌和内分泌调节； 3.确定COUP-TFII在子宫内膜间质功能调节中的作用；4.确定COUP-TFII在子宫内膜间质细胞中的调控分子途径。

Description (provided by applicant): The overall objective of this proposal is to define the essential molecular mechanisms that underlie the preparation of the uterus to support pregnancy, in general, and specifically, the involvement of the orphan nuclear receptor transcription factor, COUP-TF II, in this process. Utilizing the progesterone receptor knockout, PRKO, mouse in combination with DNA microarray technology, we have identified the Indian Hedgehog, Ihh, morphogen pathway as being one of the earliest pathways responsive to progesterone. One of the downstream targets of the Ihh pathway is the orphan nuclear receptor transcription factor, COUP-TF II. In the mouse, COUP-TF II expression is initiated in the sub-epithelial stroma of the endometrium prior to the window of receptivity for embryo implantation and if pregnancy is established during the decidual transformation of the endometrial stroma cells. Functionally, COUP-TF II is a critical factor regulating development. Ablation of COUP-TF II in mice results in early embryo lethality. Mice heterozygous for ablation of COUP-TF II are sub-fertile partially due to impairment of the ability of the uterus to support implantation. In humans, DNA microarray analysis of endometrial biopsy tissue demonstrated that, similar to the mouse, COUP-TF II expression is increased in the human uterus during the implantation period. COUPTF II expression has also been observed in endometriotic tissue and has been hypothesized to play a protective role in regulating hormone production and growth of this diseased tissue. These laboratory and clinical observations indicate that COUP-TF II plays an important role in normal uterine function and in regulating uterine biology in diseased states. Given the critical role COUP-TF II plays in mouse uterine biology, as well as its expression at critical times in the human endometrium, this proposal will translate these laboratory findings into an investigation of the regulation and role of COUP-TF II in the human uterus during pregnancy and in pathological states. This will be accomplished by the following: 1. Defining the stage and cell specific pattern of COUP-TF II in the human endometrium; 2. Determining the paracrine and endocrine regulation of COUP-TF II expression in human endometrial stromal cells; 3. Determining the role of COUP-TF II in the regulation of endometrial stromal function; 4. Identifying the molecular pathways regulated by COUP-TF II in the endometrial stroma cells.