Ophan Nuclear Receptor COUPTF-II in Endometrial Biology

描述（由申请方提供）：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，一般而言，特别是孤儿核受体转录因子COUP-TF II参与该过程。利用孕酮受体敲除，PRKO，小鼠与DNA微阵列技术相结合，我们已经确定了印度刺猬，Ihh，形态发生蛋白途径是最早的途径之一，孕酮响应。Ihh途径的下游靶标之一是孤儿核受体转录因子COUP-TF II。在小鼠中，COUP-TF II表达起始于胚胎接受窗口之前的子宫内膜上皮下基质中 着床和如果在子宫内膜的蜕膜转化期间妊娠 间质细胞在功能上，COUP-TF II是调节发育的关键因子。小鼠COUP-TF II的消融导致早期胚胎死亡。COUP-TF II消融杂合子小鼠生育力低下，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，与小鼠相似，COUP-TF II表达在人类子宫着床期间增加。COUPTF II的表达也已在乳腺癌组织中观察到，并被假设在调节激素产生和该病变组织的生长中起保护作用。这些实验室和临床观察表明，COUP-TF II在正常子宫功能和疾病状态下调节子宫生物学方面发挥重要作用。考虑到COUP-TF II在小鼠子宫生物学中的关键作用，以及其在人类子宫内膜关键时刻的表达，该提案将这些实验室发现转化为COUP-TF II在妊娠期间和病理状态下在人类子宫中的调节和作用的研究。这将通过以下方式实现：1.确定COUP-TF II在人子宫内膜中的阶段和细胞特异性模式; 2.人子宫内膜间质细胞COUP-TF Ⅱ表达的旁分泌和内分泌调节 3.确定COUP-TF II在调节子宫内膜间质功能中的作用; 4. COUP-TF II在子宫内膜间质细胞中调控的分子通路的鉴定

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.