PREGNANCY-SPECIFIC MODULATION OF NK CELLS

这项研究的目的是进一步加深我们对怀孕的建立和维持的理解。我们的重点是了解发源于发育中的绒毛膜尿囊性胎盘滋养细胞的信号的作用，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胎外结构之间的界面，并精心制作与催乳素（PRL）相关的蛋白家族。PRL家族的一个成员，PRL样蛋白- a (PLP-A)，由滋养细胞合成，直接结合并调节子宫内自然杀伤细胞的活性。自然杀伤细胞是免疫监视的一部分，对各种细胞群具有细胞分裂活性，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膜尿囊胎盘近端子宫胎盘间室中表现出时间和空间特异性的出现模式。在表型上，子宫自然杀伤细胞活性谱经历了妊娠依赖性转化。到妊娠中期，子宫自然杀伤细胞表现出最小的细胞溶解活性，并表达一系列独特的分泌产物。这些自然杀伤细胞功能的调整促进了怀孕的建立和维持。我们假设滋养细胞特异性产物PLP-A指导子宫自然杀伤细胞行为的妊娠依赖性变化，从而促进妊娠的建立和维持。在本研究项目中，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基因零突变小鼠的生理后果。计划的研究利用细胞和分子以及体外和体内策略。该实验的数据将提高我们对滋养层细胞-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大的见解，并将对我们理解在免疫疾病和癌症等异常过程中自然杀伤细胞功能的控制具有重要意义。

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.