ORIGINS AND FUNCTIONS OF UTERINE NATURAL KILLER CELLS IN PREGNANCY

妊娠期子宫自然杀伤细胞的起源和功能

• 批准号: 9980287
• 负责人: Wayne M. Yokoyama
• 金额: $ 55.32万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-13 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980287
• 关键词: Activities of Daily Living; Affect; Biological; Blood Vessels; CRISPR/Cas technology; Cellular biology; Clinical; Decidual Cell Reactions; Dependence; Epidemiology; Evolution; Family; Fetal Tissues; Fetus; Gene Targeting; Genes; Genotype; Goals; Home environment; Human; Individual; Knockout Mice; Laboratories; Lead; Leukocytes; Ligands; Maternal-Fetal Exchange; Mus; Natural Killer Cells; Organ; Outcome; Placentation; Play; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Pregnant Uterus; Process; Property; Receptor Cell; Reproduction; Role; Time; Tissues; Uterus; epidemiology study; experimental study; fetal; genome editing; in vivo; insight; killer immunoglobulin-like receptor; pregnancy disorder; pregnant; receptor; transcription factor

Epidemiological studies have associated preeclampsia outcomes with genotypes of receptors on maternal natural killer (NK) cells, and genotypes of their cognate HLA class I (HLA-I) ligands in fetuses. These clinical findings have been replicated and strongly suggest that uterine NK (uNK) cells, the most abundant leukocytes at the maternal-fetal interface, specifically use their receptors to recognize HLA-I on fetal tissues, thereby playing vital roles in normal placentation, probably by affecting the vasculature which is abnormal in preeclampsia. Although it is challenging to study these possibilities in human reproduction, and we acknowledge that there are species-specific differences between human and mouse pregnancy, studies of mouse NK cells can yield important conceptual insight, as demonstrated numerous times previously in NK cell biology. Recent studies from the applicant's laboratory indicate that mouse organs, including the virgin uterus, contain both circulating “conventional” NK (cNK) cells and tissue-resident NK (trNK) cells that reside in the organ and do not recirculate. cNK and trNK cells from different organs represent distinct lineages of NK cells because they have differences in transcription factor dependencies. Moreover, cNK and trNK cells have different functional capacities. Finally, the Ly49 family of receptors are the functional equivalents to the human NK cell receptors implicated in preeclampsia. These considerations lead to the following proposed Specific Aims: 1) Determine contributions of cNK and trNK cells to uNK cells in pregnancy and decidualization; 2) Examine transcription factor dependence of uNK cells; and 3) Determine role of Ly49 receptors in pregnancy. Thus, these studies will provide major insight into the role of uNK cells in pregnancy, the major long-term objective of this proposal.

流行病学研究将先兆子痫的结局与母体子宫内膜上受体的基因型联系起来 自然杀伤（NK）细胞，以及它们在胎儿中的同源HLA I类（HLA-I）配体的基因型。这些临床 研究结果已被复制，并强烈表明子宫NK（uNK）细胞，最丰富的白细胞， 在母胎界面，特异性地使用它们的受体来识别胎儿组织上的HLA-I，从而 在正常的胎盘形成中起着重要作用，可能是通过影响血管系统，而血管系统在正常的胎盘形成中是异常的。 先兆子痫尽管研究人类生殖的这些可能性具有挑战性， 承认人类和小鼠怀孕之间存在物种特异性差异， 小鼠NK细胞可以产生重要的概念性见解，正如以前在NK细胞中多次证明的那样， 细胞生物学申请人实验室最近的研究表明，小鼠器官，包括处女， 子宫，含有循环“常规”NK（cNK）细胞和组织驻留NK（trNK）细胞， 在器官中，不循环。来自不同器官的cNK和trNK细胞代表不同的NK谱系 细胞，因为它们在转录因子依赖性方面存在差异。此外，cNK和trNK细胞具有 不同的功能能力。最后，Ly 49受体家族是与人受体的功能等同物。 NK细胞受体参与先兆子痫。这些考虑导致提出以下具体建议： 目的：1）确定cNK和trNK细胞在妊娠和蜕膜化中对uNK细胞的贡献; 2） 检查uNK细胞的转录因子依赖性;和3）确定Ly 49受体在妊娠中的作用。 因此，这些研究将为uNK细胞在妊娠中的作用提供重要的见解，这是主要的长期影响因素。 这项提案的目的。