Uterine natural killer cells, their expression and function through peptides and impact on reproductive success.

子宫自然杀伤细胞，它们通过肽的表达和功能以及对生殖成功的影响。

• 批准号: MR/T007133/1
• 负责人: Ka Ying Bonnie Ng
• 金额: $ 32.4万
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT007133%2F1
• 关键词: Uterine; natural; killer; cells; their

Human reproduction is inefficient and abnormal implantation of the embryo into the mother's womb (or 'uterus') is a leading cause of maternal and foetal morbidity and mortality worldwide. After fertilisation of the egg, the embryo maintains a continuous reciprocal communication with the mother. The embryo implants into the lining of the mother's womb, also known as the 'endometrium' at the start of pregnancy. Failure in the orchestration of this process leads to reproductive failures including subfertility (inability to conceive for >1year), recurrent miscarriages (>2 consecutive early pregnancy losses), and recurrent implantation failure (>1 failed in-vitro fertilisation cycles despite good quality embryos replaced). Reproductive failures and later pregnancy complications, including low birth weight, preterm delivery, and pre-eclampsia are thought to result from poor implantation/ placental development. Current management options for these women are ineffective and prevention strategies are limited.Natural killer (NK) cells are cells of the innate immune system and are key regulators of implantation. During implantation, the outer layer of cells in the developing embryo (fetal trophoblast cells) invade the endometrium to gain access to nutrients. NK cells within the womb have surface receptors, called Killer Cell Immunoglobulin-like Receptors (KIRs), which interact with Human Leukocyte Antigen (HLA) receptors on fetal trophoblast cells, maintaining fine control of the depth of invasion into the mother's womb. HLA is a complex that helps the immune system distinguish the body's own proteins from foreign proteins (such as viruses and bacteria). Specific combinations of KIRs and HLA pairs have been shown to impact pregnancy outcomes. For example, the combination of KIR2DS1 (an activating receptor for uterine NK cells) in the mother, in association with fetal HLA-C has been shown to be protective against pregnancy complications. This suggests that pregnancy success is determined by the interaction between NK cells within the mother's womb and fetal tissue.My objective is to assess how activating receptors, such as KIR2DS1, expressed on NK cells in the endometrium contribute to successful pregnancy. I will obtain endometrium from women known to suffer from reproductive failures during the 'implantation window', a specific time point during a menstrual cycle in which the womb is programmed to respond and prepare for a possible pregnancy. These samples will be processed in the laboratory to characterise activating and inhibitory receptors on NK cells, and understand their function. Their potential to secrete various cytokines (small proteins important in cell-to-cell communication) will also be assessed. Work from our lab has also shown that naturally occurring small biological molecules (or 'peptides') derived from certain proteins are displayed on the cell surface by HLA, which has the potential to activate NK cells by binding specifically to KIRs. I will examine whether interactions of activating KIR on NK cells in the womb with fetal trophoblast cells are modulated by peptides to influence pregnancy success.For the first time, we will be able to understand the interactions between the mother's NK cells in the womb and specific peptides on the fetal trophoblast. This will help us understand the immunological mechanisms of healthy implantation and placental development and may help in the development of new therapies or target patients to specific treatments. This project will take place at the University of Southampton led by Professor Cheong, specialist in reproductive medicine and Professor Salim Khakoo, an expert in NK cells in collaboration with Professor Ashley Moffett's group at the University of Cambridge, who are world leaders in immunology research within pregnancy. A MRC Clinical Research Training Fellowship will provide funding for Dr. Ng to become a PhD Research Fellow to work on this project.

人类生殖是低效的，胚胎异常植入母亲的子宫（或“子宫”）是全世界孕产妇和胎儿发病率和死亡率的主要原因。卵子受精后，胚胎与母体保持持续的相互交流。胚胎植入到母亲的子宫内膜中，也被称为怀孕开始时的“子宫内膜”。这一过程的协调失败会导致生殖失败，包括生育力低下（无法怀孕> 1年），复发性流产（>2次连续早孕失败）和复发性着床失败（>1次体外受精失败，尽管更换了优质胚胎）。生殖失败和后期妊娠并发症，包括低出生体重、早产和先兆子痫，被认为是着床/胎盘发育不良所致。目前对这些妇女的管理方案是无效的，预防策略是有限的。自然杀伤（NK）细胞是先天免疫系统的细胞，是植入的关键调节器。在着床过程中，发育中的胚胎外层细胞（胎儿滋养层细胞）侵入子宫内膜以获得营养。子宫内的NK细胞具有称为杀伤细胞免疫球蛋白样受体（KIR）的表面受体，其与胎儿滋养层细胞上的人类白细胞抗原（HLA）受体相互作用，维持对侵入母亲子宫的深度的精细控制。HLA是一种复合物，可以帮助免疫系统区分人体自身的蛋白质和外来蛋白质（如病毒和细菌）。KIR和HLA对的特定组合已被证明会影响妊娠结局。例如，母亲体内KIR 2DS 1（一种子宫NK细胞的活化受体）与胎儿HLA-C的结合已显示出对妊娠并发症的保护作用。这表明妊娠成功是由母亲子宫内的NK细胞和胎儿组织之间的相互作用决定的。我的目的是评估子宫内膜中NK细胞上表达的激活受体（如KIR 2DS 1）如何有助于成功妊娠。我将从已知在“植入窗口”期间患有生殖失败的女性中获得子宫内膜，这是月经周期中的一个特定时间点，在这个时间点上，子宫被编程为做出反应并为可能的怀孕做准备。这些样本将在实验室进行处理，以检测NK细胞上的激活和抑制受体，并了解其功能。还将评估它们分泌各种细胞因子（在细胞间通讯中重要的小蛋白质）的潜力。我们实验室的工作还表明，源自某些蛋白质的天然小生物分子（或“肽”）通过HLA展示在细胞表面，HLA具有通过特异性结合KIR激活NK细胞的潜力。我将研究子宫内NK细胞上的激活KIR与胎儿滋养层细胞的相互作用是否受到肽的调节，从而影响妊娠成功。我们将首次能够了解母亲子宫内NK细胞与胎儿滋养层细胞上特定肽之间的相互作用。这将有助于我们了解健康着床和胎盘发育的免疫学机制，并可能有助于开发新的治疗方法或针对特定患者进行治疗。该项目将在南安普顿大学进行，由生殖医学专家Cheong教授和NK细胞专家Salim Khakoo教授领导，并与剑桥大学阿什利莫菲特教授的小组合作，他们是怀孕期间免疫学研究的世界领导者。MRC临床研究培训奖学金将为吴博士提供资金，使其成为博士研究员，从事该项目。