PROJECT 1 - Endometrial Steroid Receptor Coregulator-2 in Peri-Implantation Biolo

协调控制雌激素（E2）和孕激素（P4）的协同和拮抗作用， 这是获得子宫内膜容受性和成功胚胎植入所必需的。类固醇受体 辅助调节因子-2（SRC-2）是SRC家族中的一员，在小鼠子宫内膜异位症中起重要作用 感受性和蜕膜化。SRC-2可作为P4受体（PR）的共激活物或共阻遏物发挥作用。 介导的小鼠子宫中的转录反应。重要的是，最近的研究表明，（a）SRC-2是 在人中与在小鼠中观察到的相同子宫内膜细胞类型中表达;（B）敲低 SRC-2阻断培养的人子宫内膜基质细胞的蜕膜化;和（c）SRC-2的调节异常。 在诊断为子宫内膜异位症的患者的在位子宫内膜中观察到正常的SRC-2表达。 总之，这些发现表明SRC-2是类固醇激素依赖性的一种有效的共调节因子。 子宫内膜的功能，其失调可能与子宫内膜的病理，如 子宫内膜异位症基于上述，提出以下假设：类固醇受体 辅调节子-2是P4信号传导的必需辅调节子，其控制增殖和 子宫内膜容受性和蜕膜化所需的不同程序。推进这一 假设，我们将（1）描述支持小鼠SRC-2的细胞和分子机制 在正常子宫内膜对类固醇激素暴露的反应中的作用;（2）确定人类 SRC-2在正常子宫内膜对类固醇激素暴露的反应中的重要性;（3）建立SRC-2在正常子宫内膜对类固醇激素暴露的反应中的重要性。 SRC-2在正常P4诱导的子宫内膜破裂中的非程序性上调表达 建立妊娠所需的反应;和（4）确定SRC-2在P4中的作用 控制肿瘤病变生长。最先进的小鼠遗传学，慢病毒技术解除管制 SRC-2在人子宫内膜功能和子宫内膜异位症的创新实验模型中的表达， 明智设计的转录本分析和microRNA阵列方法将构成许多 这些创新方法将用于成功实现我们的既定目标。通过解决 传统方法的局限性，这项研究计划将大大扩大子宫内膜领域 协同调节研究远远超出了目前的描述性分析模式，以一个更疑问的领域， 调查这些研究的结果不仅有助于我们进一步了解子宫内膜 辅助调节子功能，而且还有助于设计用于不孕症的新的诊断方法和/或疗法。

Coordinated control of the synergistic and antagonistic actions of estrogen (E2) and progesterone (P4) is required to achieve endometrial receptivity and successful embryo implantation. Steroid receptor coregulator-2 (SRC-2), a member of the SRC family of coregulators, is essential for murine endometrial receptivity and decidualization. SRC-2 can act as a coactivator or as a corepressor of P4 receptor (PR) mediated transcriptional responses in the murine uterus. Importantly, recent studies show that (a) SRC-2 is expressed in the same endometrial cell-types in the human as observed in the mouse; (b) knockdown of SRC-2 blocks the decidualization of human endometrial stromal cells in culture; and (c) dysregulation of normal SRC-2 expression is observed in the eutopic endometrium of patients diagnosed with endometriosis. Together, these findings suggest that SRC-2 represents a potent coregulator of steroid hormone-dependent endometrial function in the human, and that its dysregulation may be linked to endometrial pathologies, such as endometriosis. Based on the aforementioned, the following hypothesis is proposed: Steroid receptor coregulator-2 is an essential coregulator of P4 signaling which controls proliferative and differentiatlve programs required for endometrial receptivity and decidualization. To advance this hypothesis, we will (1) delineate the cellular and molecular mechanisms which underpin murine SRC-2 action in normal endometrial responses to steroid hormone exposure; (2) define the importance of human SRC-2 in normal endometrial responses to steroid hormone exposure; (3) establish the importance of unscheduled upregulation of SRC-2 expression in the breakdown of normal P4 induced endometrial responses that are required for the establishment of pregnancy; and (4) determine the role of SRC-2 in P4 control of endometriotic lesion growth. State-of-the-art mouse genetics, lentiviral technology to deregulate SRC-2 expression in an innovative experimental model for human endometrial function and endometriosis, and judiciously designed transcript profiling and microRNA array approaches will constitute a number of the inventive methodologies that will be used to successfully execute our stated aims. By addressing the limitations of conventional methods, this research program will significantly expand the field of endometrial coregulator study far beyond the current descriptive mode of analysis to a more interrogative field of investigation. Results from these studies promise not only to further our understanding of endometrial coregulator function but also aid in the design of novel diagnostic approaches and/or therapies for infertility.