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.

流行病学研究已经将先兆子痫的结果与受体的基因型相关联 天然杀手（NK）细胞及其同源I类（HLA-I）配体的基因型。这些临床 发现已被复制，并强烈建议子宫NK（UNK）细胞，最丰富的白细胞 在母亲界面上，专门使用其接收器识别胎儿组织的HLA-I 在正常位置中发挥至关重要的作用，可能是通过影响异常的脉管系统 先兆子痫 承认人与小鼠怀孕之间存在特定规范的差异，研究 小鼠NK细胞可以产生重要的概念见解，如先前在NK中的多次证明 细胞生物学。申请人的实验室指标的最新研究表明，包括处女在内的小鼠器官 子宫，既包含循环的“常规” NK（CNK）细胞和居住的居民NK（TRNK）细胞 在器官中，不要再循环。来自不同器官的CNK和TRNK细胞代表NK的不同线条 细胞是因为它们在转录因子依赖性方面有差异。此外，CNK和TRNK细胞具有 不同的功能能力。最后，LY49接收器家族是人类的功能等效物 在先兆子痫中实现的NK细胞受体。这些考虑导致以下提出的特定 目的：1）确定CNK和TRNK细胞在怀孕和决定性化中对UNK细胞的贡献； 2） 检查UNK细胞的转录因子依赖性； 3）确定Ly49受体在妊娠中的作用。 这是这些研究将为UNK细胞在怀孕中的作用提供重大洞察力，这是主要的长期长期 该提议的目标。