PROJECT 4 - The Role of COUP - TFII in Endometrial Biology

这项建议的总体目标是确定基本的分子机制，基础的作用 COUP-TFII调节子宫内膜功能，准备子宫以支持妊娠， 这些机制的改变如何导致子宫内膜功能障碍，如子宫内膜异位症。期间 在上一个资助期间，我们已经证明，使用基因工程小鼠模型，COUP-TFII是 通过控制子宫支持胚胎的能力来调节怀孕的开始 依恋、入侵和妊娠的维持。COUP-TFII通过以下方式调节这些过程 控制子宫上皮细胞对雌激素的敏感性，以及子宫基质细胞增殖， 通过调节Wnt和表皮生长因子（EGF）信号传导， 途径。使用原代人子宫内膜组织，我们已经证明了这一途径在子宫内膜癌中是保守的。 人子宫内膜和COUP-TFII对于人子宫内膜间质细胞的能力至关重要， 体外分化。本提案的目标是研究COUP-TFII如何调节子宫内膜 上皮ER信号和间质Wnt和EGFR信号在调节子宫内膜功能和 功能障碍1 . COUP-TFII的重要性 将研究子宫内膜上皮E2敏感性在控制子宫容受性中的调节。2.的 将确定COUP-TFII在调节人子宫内膜雌激素敏感性中的作用。3.的 COUP-TFII调控人子宫内膜靶基因表达的分子机制 将研究基质细胞。4. EGFR在PR-1hh-COUP-TFII轴调节细胞凋亡的能力中的作用 将研究子宫内膜功能。这些目标的实现将定义分子 调节子宫内膜功能和功能障碍的机制。

The overall objective of this proposal is to define the essential molecular mechanisms that underlie the role of COUP-TFII in the regulation of endometrial function in preparation of the uterus to support pregnancy and how alteration of these mechanisms results in endometrial dysfunction, such as endometriosis. During the last funding period, we have demonstrated, using genetically engineered mouse models, that COUP-TFII is critical in regulating the initiation of pregnancy by controlling the ability of the uterus to support embryo attachment, invasion, and the maintenance of pregnancy. COUP-TFII regulates these processes by controlling uterine epithelial cell sensitivity to estrogen, as well as, uterine stromal cell proliferation, vascularization, and differentiation by regulating Wnt and Epidermal Growth Factor (EGF) signaling pathways. Using primary human endometrial tissue, we have shown that this pathway is conserved in the human endometrium and COUP-TFII is critical for the ability of human endometrial stromal cells to differentiate in vitro. The goal of this proposal will be to investigate how COUP-TFII regulates endometrial epithelial ER signaling and stromal Wnt and EGFR signaling in the regulation of endometrial function and dysfunction. This will be accomplished by achieving the following aims: 1 .The importance of COUP-TFII regulation of endometrial epithelial E2 sensitivity in controlling uterine receptivity will be investigated. 2. The role of COUP-TFII in the regulation of human endometrial estrogen sensitivity will be determined. 3. The molecular mechanism by which COUP-TFII regulates the expression of target genes in human endometrial stromal cells will be investigated. 4. The role of EGFR in the ability of the PR-lhh-COUP-TFII axis to regulate endometrial function will be investigated. Accomplishment of these aims will define the molecular mechanisms regulating endometrial function and dysfunction.