Decidual Cell Adaptations to Physiological Stressors

描述(申请人提供)：妊娠的建立和维持需要一种特殊的母体组织的适当发育，称为蜕膜。蜕膜细胞通过孕酮的作用产生于子宫间质，与胎盘结构形成密切的关系，促进胚胎的发育。黄体酮的作用部分是通过激活转录调节因子CCAAT/增强子结合蛋白(3(C/EBP)来实现的。蜕膜细胞的重要功能之一是其激素/细胞因子的产生能力。催乳素相关激素/细胞因子(PRL)是蜕膜细胞重要的分泌蛋白，包括蜕膜催乳素相关蛋白(DPrP)。子宫胎盘PRL家族参与了伴随妊娠的子宫炎性细胞反应的调节。我们认为DPrP调节宫内对炎症/生理应激源的反应，包括抑制蜕膜细胞应激和维持血管完整性。DPrP调节失调导致蜕膜细胞应激(包括CHOP上调)和血管不稳定。CHOP是一种已知的C/EBP活性的抑制剂，它的激活可能会损害蜕膜细胞的功能。蜕膜细胞功能和血管完整性的破坏增加了妊娠失败的易感性。在这个研究项目中，我们计划研究蜕膜细胞对生理应激源的适应调节。在第一个具体目标中，我们研究了影响和调节蜕膜对生理应激源适应的因素。具体目标2评估DPrP和人类PRL在调节对生理应激源的适应中的作用。第三个目的是研究CHOP在暴露于生理应激源后蜕膜细胞功能失调中的作用。每个目标都是完全独立的，将在授权期的第一年年初开始，并将并行进行到拟议的授权期结束。这项计划中的研究利用了细胞和分子以及体外和体内的策略。从拟议的实验中获得的数据将提高我们对蜕膜细胞信号的性质以及蜕膜PRL家族在调节胎盘中的作用的理解。这些发现将为与妊娠失败相关的发育障碍的病因学提供相当大的洞察力，并将对我们对生理应激源适应的理解产生重要的影响。

DESCRIPTION (provided by applicant): The establishment and maintenance of pregnancy require appropriate development of a specialized maternal tissue, referred to as decidua. Decidual cells arise from uterine stroma via the actions of progesterone, form intimate relationships with placental structures, and facilitate the development of the embryo. The actions of progesterone are mediated, in part, through activation of the transcriptional regulator CCAAT/enhancer binding protein (3 (C/EBP¿). Among the important functions of decidual cells are their hormone/cytokine producing capabilities. Hormone/cytokines related to prolactin (PRL) are prominent decidual cell secretory proteins and include decidual prolactin-related protein (dPRP). The uteroplacental PRL family has been implicated in the regulation of uterine inflammatory cell responses accompanying pregnancy. We propose that dPRP modulates intrauterine responses to inflammation/physiological stressors, including inhibiting decidual cell stress and preserving vascular integrity. Dysregulation of dPRP results in decidual cell stress (including upregulation of CHOP) and vascular instability. CHOP is a known inhibitor of C/EBP¿ actions, and its activation potentially compromises decidual cell function. Disruptions in decidual cell function and in vascular integrity increase susceptibility to pregnancy failure. In this research project, we plan to investigate the regulation of decidual cell adaptations to physiological stressors. In Specific Aim No. 1 we investigate factors impacting and mediating decidual adaptations to physiological stressors. Specific Aim No. 2 assesses the role of dPRP and human PRL in the regulation of adaptations to physiological stressors. The third Aim investigates the role of CHOP in the dysregulation of decidual cell function following exposure to physiological stressors. Each Aim is entirely independent and will be started at the beginning of year one of the grant period and will proceed in parallel through the end of the proposed grant period. The planned research utilizes cellular and molecular and in vitro and in vivo strategies. Data derived from the proposed experimentation will improve our understanding of the nature of decidual cell signaling and the role of the decidual PRL family in the regulation of viviparity. These findings will provide considerable insight into the etiology of developmental disorders associated with pregnancy failure and will also have important ramifications on our understanding of adaptations to physiological stressors.