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.

流行病学研究发现子痫前期结局与母体受体基因型有关