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: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=629142
• 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。每月在月经周期和整个怀孕期间，它是一个强烈的重建的地方。然而，参与这种重塑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，致力于研究这些机制，旨在更好地了解子宫内膜重塑和正常生殖功能。在短期内，我们计划研究子宫内膜重塑过程，这对胚胎在子宫内成功着床和维持妊娠至关重要，称为脱个体化。在这一过程中，子宫内膜中的一种细胞——子宫内膜基质细胞（endometrial stromal cells, ESCs）经历了一系列的变化：它们必须分化为蜕膜细胞，同时获得适应各种死亡诱导信号的生存能力。两种细胞内因子p53和PAX8在去个体化过程中在ESCs中积累；然而，它们表达的精确调控及其在这种情况下的作用尚不清楚。根据之前的研究和我们的初步结果，可以假设PAX8活性以p53依赖的方式决定了去个体化过程中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，使用大鼠的去个体化模型，它非常模仿人类的去个体化过程。利用该大鼠模型，我们拟探讨：1)PAX8的表达和活性是否受到ESCs中PKA活性的正调控，并在camp诱导的去个性化开始时增加；2) PAX8调控p53基因表达，促进其在去个体化ESCs中的积累；3) PAX8-p53轴在去个性化时调节ESCs的存活和分化。这些研究将使我们首次确定PAX8作为ESC去个体化的关键调节因子的作用，并揭示其p53依赖的作用模式。这是对正常子宫内膜重塑和生殖功能机制的全面理解迈出的重要一步。