PREGNANCY-SPECIFIC MODULATION OF NK CELLS

这项研究的目的是进一步了解怀孕的建立和维持。 我们专注于了解起源于发育中的绒毛尿囊胎盘滋养层细胞的信号的作用，并针对位于子宫胎盘室内的自然杀伤细胞。 滋养层细胞位于母体和胚外结构之间的界面，并阐述了与催乳素（PRL）相关的蛋白质家族。 PRL家族的一个成员，PRL样蛋白-A（PLP-A），由滋养层细胞合成，并直接结合和调节位于子宫中的自然杀伤细胞的活性。 自然杀伤细胞是免疫监视的一部分，对各种细胞群体具有细胞学活性，并表达各种生物效应分子。 在妊娠期间，自然杀伤细胞在发育中的绒毛尿囊胎盘近端的子宫胎盘室中表现出时间和空间特异性的外观模式。 从表型上看，子宫自然杀伤细胞活性谱经历妊娠依赖性转化。 到妊娠中期，子宫自然杀伤细胞显示出最小的细胞溶解活性，并表达一系列独特的分泌产物。 自然杀伤细胞功能的这些调整有助于建立和维持妊娠。 我们假设滋养层细胞特异性产物PLP-A指导子宫自然杀伤细胞行为的妊娠依赖性变化，并在此过程中促进妊娠的建立和维持。 在这个研究项目中，我们建议评估PLP-A对自然杀伤细胞活性的作用，并检查产生PLP-A基因无效突变小鼠的生理后果。 计划中的研究利用细胞和分子以及体外和体内策略。 从拟议的实验中获得的数据将提高我们对滋养层自然杀伤细胞信号传导的性质以及子宫自然杀伤细胞在妊娠状态的建立和维持中的作用的理解。 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多的见解，也将对我们理解自然杀伤细胞功能在异常过程中的控制产生重要影响，如免疫疾病和癌症。

The goal of this research is to further our understanding of the establishment and maintenance of pregnancy. We focus on understanding the actions of signals originating in trophoblast cells of the developing chorioallantoic placenta and targeted toward Natural Killer cells located within the uteroplacental compartment. Trophoblast cells are situated at the interface between maternal and extraembryonic structures and elaborate a family of proteins related to prolactin (PRL). One member of the PRL family, PRL-like protein-A (PLP-A), is synthesized by trophoblast cells and directly binds and modulates the activity of Natural Killer cells positioned in the uterus. Natural Killer cells are a part of the immune surveillance, are cytoloytically active toward various cell populations, and express an assortment of bioeffector molecules. During gestation, Natural Killer cells exhibit temporal- and spatial-specific patterns of appearance within the uteroplacental compartment proximal to the developing chorioallantoic placenta. Phenotypically, the spectrum of uterine Natural Killer cells activities undergoes a gestational- dependent transformation. By midpregnancy, uterine Natural Killer cells show minimal cytolytic activities and express a unique array of secretory products. These adjustments in Natural Killer cell function facilitate the establishment and maintenance of pregnancy. We hypothesize that the trophoblast cell-specific product, PLP-A, directs gestational-dependent changes in the behavior of uterine Natural Killer cells and in doing so facilitates the establishment and maintenance of pregnancy. In this research project, we propose to evaluate the actions of PLP- A on Natural Killer cell activities and to examine the physiological consequences of creating mice with a null mutation of the PLP-A gene. 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 trophoblast-Natural Killer cell signaling and the role of uterine Natural Killer cells in the establishment and maintenance of the gestational state. These findings will provide considerable insight into the etiology of developmental disorders associated with pregnancy failure and will also have significant implications on our understanding of the control of Natural Killer cell functions in aberrant processes such as immune disease and cancer.