GREB1 Action in Endometrial Function and Dysfunction

 描述（由申请人提供）：即使囊胚发育正常，子宫内膜中基质细胞向蜕膜细胞的分化不足（称为蜕膜化）也会导致着床失败或早期胚胎流产。虽然在子宫内膜生理学中支持类固醇激素作用的许多细胞机制已经明确，但关于在蜕膜化过程中控制或介导类固醇激素反应的辅调节因子和信号通路存在显著的知识缺口。这种知识差距是重要的，因为如果没有对胚胎植入这方面的新的机制见解，将无法实现基于功能受损的子宫内膜诊断和/或治疗不孕症的能力。最近，我确定GREB 1作为一个孕激素反应基因和关键的诱导所需的原代人子宫内膜间质细胞培养的蜕膜化的孕激素分子靶。因此，这一发现暗示了GREB 1在这一细胞过程中的共激活剂作用。在平行研究中，我还发现GREB 1是雌激素驱动的子宫内膜异位症患者子宫内膜癌细胞增殖所必需的，表明GREB 1在雌激素依赖性子宫内膜异位症中的单独作用。基于我的初步观察，我假设GREB 1的辅激活因子功能是必需的，对于炔雌醇驱动的子宫内膜蜕膜化和雌激素依赖性子宫内膜异位症的进展。因此，我的建议计划研究GREB 1在子宫内膜功能和功能障碍中的双重作用。K99阶段将使用最近设计的小鼠模型建立GREB 1在正常子宫内膜对孕酮暴露的反应中的体内作用。这些研究将过渡到R 00部分，使用该模型来定义GREB 1在雌激素驱动的子宫内膜异位症中的致病重要性。R 00期也将决定支持GREB 1在孕酮驱动的人子宫内膜蜕膜化中的辅激活因子功能的分子机制。结合职业发展培训，其中包括指导，课程工作和演讲机会，这些研究将扩展我在子宫内膜生理学和病理生理学的培训，为在不久的将来在生殖科学领域开展独立的职业生涯提供坚实的基础。

 DESCRIPTION (provided by applicant): Even when the blastocyst develops normally, inadequate differentiation of stromal cells to decidual cells in the endometrium (termed decidualization) can lead to implantation failure or early embryo miscarriage. Although many of the cellular mechanisms that underpin steroid-hormone actions in endometrial physiology are well defined, a significant knowledge-gap exists concerning the coregulator and signaling pathways that control or mediate steroid-hormone responses in the decidualization process. This knowledge-gap is significant as without new mechanistic insights into this aspect of embryo implantation, the ability to diagnose and/or treat infertility based on a functionally impaired endometrium will not be realized. Recently, I identified GREB1 as a progesterone responsive gene and critical for the induction of progesterone molecular targets required for decidualization of primary human endometrial stromal cells in culture. Therefore, this finding implicates a coactivator role for GREB1 in this cellular process. In parallel studies, I also showed that GREB1 is required for estrogen-driven proliferation of endometrioma cells derived from endometriosis patients, indicating a separate role for GREB1 in estrogen-dependent endometriosis. Based on my preliminary observations, I hypothesize that the coactivator function of GREB1 is required both for progesterone-driven endometrial decidualization and for estrogen-dependent endometriosis progression. Therefore, my proposal plans to examine the dual role of GREB1 in endometrial function and dysfunction. The K99 phase will establish the in vivo role of GREB1 in normal endometrial responses to progesterone exposure using a recently engineered mouse model. These studies will transition into the R00 portion, which uses this model to define the pathogenic importance of GREB1 in estrogen-driven endometriosis. The R00 phase will also determine the molecular mechanism that underpins the coactivator function of GREB1 in progesterone-driven human endometrial decidualization. Combined with career development training, which will include mentoring, course work, and presentation opportunities, these studies will extend my training in endometrial physiology and pathophysiology to provide a strong foundation to launch an independent career in the reproductive sciences in near future.