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: 10216997
• 负责人: Wayne M. Yokoyama
• 金额: $ 55.78万
• 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/10216997
• 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; 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.

流行病学研究表明，先兆子痫的结局与母体受体的基因型有关。 自然杀伤(NK)细胞及其同源人类白细胞抗原I类(HL A-I)配体在胎儿中的基因分型。这些临床 研究结果得到了复制，并强烈表明，子宫NK(Unk)细胞是最丰富的白细胞 在母胎界面，特异性地利用它们的受体识别胎儿组织上的人类白细胞抗原-I，从而 在正常胎盘形成中发挥重要作用，可能是通过影响血管系统 先兆子痫。尽管研究人类生殖中的这些可能性是具有挑战性的，而且我们 承认人类和小鼠怀孕之间存在物种特异性差异，研究 小鼠NK细胞可以产生重要的概念洞察力，正如之前在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，包括处女在内的小鼠器官 子宫中既有循环中的“常规”NK(CNK)细胞，也有驻留在子宫中的组织驻留NK(TrNK)细胞 而且不会再循环。来自不同器官的CNK和trNK细胞代表不同的NK谱系 细胞，因为它们对转录因子的依赖程度不同。此外，CNK和trNK细胞具有 不同的功能能力。最后，Ly49受体家族在功能上等同于人类 NK细胞受体与子痫前期有关。这些考虑导致了以下拟议的具体方案 目的：1)确定CNK和trNK细胞在妊娠和蜕膜形成过程中对Unk细胞的贡献；2) 检测Unk细胞对转录因子的依赖；以及3)确定Ly49受体在妊娠中的作用。 因此，这些研究将提供对Unk细胞在妊娠中的作用的主要洞察，这是长期的主要 这项提案的目标。