Regulation and role of PAX8 in decidualizing endometrial stromal cells

子宫内膜是子宫的内层。在月经周期和整个怀孕期间，它都是紧张重塑的地方。然而，参与这种重塑的细胞和分子机制只被部分了解。我们已经建立了一个长期的研究计划，致力于研究这些机制，旨在更好地了解子宫内膜重塑和正常的生殖功能。在短期内，我们计划研究子宫内膜重塑过程，这是胚胎成功植入子宫和维持妊娠的关键，称为蜕膜化。在这个过程中，子宫内膜中的一种细胞--子宫内膜间质细胞(ESCs)经历了一系列的变化：它们必须分化为蜕膜细胞，同时获得对各种死亡诱导信号的生存能力。P53和PAX8这两种细胞内因子在蜕膜化过程中在ESCs中积累；然而，它们的表达及其在这一背景下的作用的确切调控尚不清楚。根据以前的研究和我们的初步结果，可以假设PAX8的活性以一种依赖于P53的方式决定蜕膜化过程中ESC的完整性和功能。我们有一个独特的机会来验证这一假设，使用在老鼠身上的蜕膜化模型，它非常接近于人类的蜕膜化过程。利用这一大鼠模型，我们建议研究：1)PAX8的表达和活性是否受胚胎干细胞中PKA活性的正向调节，并在cAMP诱导的蜕膜化开始时增加；2)PAX8调节P53基因的表达并促进其在蜕膜化的ESCs中的积累；3)该PAX8-P53轴调节蜕膜化时ESCs的生存和分化。这些研究应该使我们第一次确定PAX8作为ESC蜕膜化的关键调节因子的作用，并揭示其依赖于P53的作用模式。这是通向深入理解正常子宫内膜重塑和生殖功能的机制的重要的第一步。

The endometrium is the inner lining of the uterus. Monthly during the menstrual cycle and also throughout pregnancy, it is the site of an intense remodelling. The cellular and molecular mechanisms involved in this remodelling, however, are only partially understood. We have established a long-term research program dedicated to the investigation of these mechanisms, aiming to gain a better understanding of endometrium remodelling and normal reproductive function. In the short term, we plan to examine an endometrial remodelling process which is crucial for successful implantation of the embryo in the uterus and for maintenance of pregnancy, called decidualization. During this process, one type of cells in the endometrium, the endometrial stromal cells (ESCs), undergo a series of changes: they must differentiate into decidual cells, and at the same time acquire the ability to survive to various death-inducing signals. p53 and PAX8, two intracellular factors, accumulate in ESCs during decidualization; however, the precise regulation of their expression and their role in this context are unclear. Based on previous studies and on our preliminary results, it can be hypothesized that PAX8 activity dictates ESC integrity and function during decidualization, in a p53-dependent manner. We have a unique opportunity to verify this hypothesis using a model of decidualization in the rat, which closely mimics the decidualization process in humans. Using this rat model, we propose to investigate if: 1) PAX8 expression and activity is positively regulated by PKA activity in ESCs and is increased at the beginning of cAMP-induced decidualization; 2) PAX8 regulates p53 gene expression and promotes its accumulation in decidualizing ESCs; 3) this PAX8-p53 axis regulates survival and differentiation of ESCs at the time of decidualization. These studies should allow us to identify for the first time a role for PAX8 as a key regulator of ESC decidualization, and to uncover its p53-dependent mode of action. This represents an important initial step towards a thorough comprehension of the mechanisms underlying normal endometrial remodelling and reproductive function.