Decidual Cell Adaptations to Physiological Stressors

描述（由申请人提供）：怀孕的建立和维持需要一个特殊的母体组织的适当发育，称为蜕膜。蜕膜细胞通过黄体酮的作用从子宫基质中产生，与胎盘结构形成密切关系，促进胚胎发育。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¿））介导的。蜕细胞的重要功能之一是它们产生激素/细胞因子的能力。催乳素相关激素/细胞因子是重要的蜕膜细胞分泌蛋白，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症细胞反应的调节。我们认为，dPRP调节子宫内对炎症/生理应激源的反应，包括抑制蜕膜细胞应激和保持血管完整性。dPRP的失调导致蜕细胞应激（包括CHOP的上调）和血管不稳定。CHOP是一种已知的C/EBP抑制剂，它的激活可能会损害细胞的功能。蜕细胞功能和血管完整性的破坏增加了妊娠失败的易感性。在本研究项目中，我们计划研究蜕细胞对生理应激源的适应调节。在Specific Aim No. 1中，我们研究了影响和介导个体对生理应激源适应的因素。具体目标2评估dPRP和人类PRL在调节生理应激源适应中的作用。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。每个目标是完全独立的，将在资助期的第一年开始，并将并行进行，直到建议的资助期结束。计划的研究利用细胞和分子以及体外和体内策略。从实验中得到的数据将提高我们对蜕细胞信号传导的本质和蜕细胞PRL家族在调控活性中的作用的理解。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见解，并将对我们对生理应激源的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.