Regulation and role of PAX8 in decidualizing endometrial stromal cells

PAX8在子宫内膜基质细胞蜕膜化中的调控及作用

• 批准号: 386602-2011
• 负责人: VanThemsche, Céline
• 金额: $ 2.99万
• 依托单位: Université du Québec à Trois-Rivières
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2013
• 资助国家: 加拿大
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=528966
• 关键词: Regulation; role; PAX8; decidualizing; endometrial

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.

子宫内膜是子宫的内层。在月经周期和整个怀孕期间每月，它是一个激烈的重塑的网站。然而，这种重塑所涉及的细胞和分子机制仅被部分理解。我们已经建立了一个长期的研究计划，致力于调查这些机制，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，我们计划检查子宫内膜重塑过程，这对胚胎在子宫内的成功植入和妊娠的维持至关重要，称为蜕膜化。在此过程中，子宫内膜中的一种细胞，子宫内膜基质细胞（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存活的能力。p53和PAX 8，两种细胞内因子，在蜕膜化过程中在ESCs中积累;然而，它们的表达的精确调节及其在这种情况下的作用尚不清楚。基于先前的研究和我们的初步结果，可以假设PAX 8活性以p53依赖的方式决定了蜕膜化过程中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，使用大鼠的蜕膜化模型，它密切模仿人类的蜕膜化过程。使用这个大鼠模型，我们建议调查：1）PAX 8的表达和活性是由PKA活性在胚胎干细胞的正调控，并在cAMP诱导的蜕膜化的开始增加; 2）PAX 8调节p53基因的表达，并促进其在蜕膜化的胚胎干细胞的积累; 3）这个PAX 8-p53轴调节胚胎干细胞的存活和分化在蜕膜化的时间。这些研究应该使我们能够首次确定PAX 8作为ESC蜕膜化的关键调节因子的作用，并揭示其p53依赖的作用模式。这代表了对正常子宫内膜重塑和生殖功能机制的全面理解的重要的第一步。