The role of uterine NK cell subsets in mediating placental implantation

子宫 NK 细胞亚群在介导胎盘着床中的作用

• 批准号: MR/X006875/1
• 负责人: Shreya Sheth
• 金额: $ 35.55万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX006875%2F1
• 关键词: role; uterine; NK; cell; subsets

The placenta implants into the lining of the womb at the beginning of pregnancy. Sometimes this does not happen properly and the pregnancy fails, for example by an early pregnancy loss. However, sometimes the placenta does implant, but incompletely. In this case, we tend to see problems at the end of pregnancy, such as pre-eclampsia, the baby not growing properly, and preterm labour. All of these can result in preterm birth, which affects 15 million babies every year, with 1 million of them dying. Of those babies that survive, one in ten will have a disability. Therefore, research into how the placenta implants has the potential not just to help women conceive, but also to improve the health of babies by avoiding them being born too soon.The lining of the womb is rich in immune cells called "uterine natural killer cells", or "uNK". These cells are thought to help the placenta to implant, but we don't yet know how. We have also recently discovered that there are three types of uNK: "uNK1", "uNK2" and "uNK3". Each of these is likely to have different roles, and perhaps only one of them is crucial for placental implantation.I want to find out which uterine NK cell subset mediates placental implantation, and how it does it.To do this, I will look at samples of the lining of the uterus from fertile women who are coming to the hospital to have a contraceptive coil fitted, compared to women attending our fertility clinic either because they have suffered more than two miscarriages, or more than two failures of implantation following IVF. I will use a technique called "flow cytometry" to look at cells from my participants one at a time and find out how many of each cell there are, and how active they are. If one particular subset is less numerous or active in women who have problems with placental implantation, that will suggest that these cells are important for implantation.To back up my conclusions from the clinic, I will also do some more intensive laboratory work. I will develop two models of placental implantation using real placental cells, one in a microchip and one in a dish. I will then see how adding pure preparations of each of the uNK subsets changes the way placental cells behave in these two models: when I add the subset that is important for implantation, it will improve the growth and migration of the placental cells. I will use these models of implantation to help me understand how the uNK help placental implantation. For example, I can block the action of certain molecules that uNK make: if these molecules are important for implantation, blocking them will make the placental cells grow and move less well. Conversely, if I add more of those molecules, and they are important for implantation, they will improve the growth and migration of the placental cells.Doing these experiments will allow me to identify which uNK subset is not working properly in clinical conditions characterised by poor placental implantation, and confirm my finding in two laboratory models of implantation. I will also use these models to begin to identify the molecules uNK make to help promote implantation. This will be an essential first step in developing diagnostic tools to identify women who are likely to suffer from disorders of pregnancy caused by insufficient implantation, and perhaps even promoting interventions that can promote placental implantation, ultimately reducing the burden of preterm birth associated with insufficient implantation.

胎盘在怀孕初期植入子宫的内层。有时，这种情况不会正常发生，导致妊娠失败，例如早期妊娠丢失。然而，有时胎盘确实植入了，但不完全。在这种情况下，我们倾向于在怀孕结束时看到问题，如先兆子痫、婴儿发育不正常和早产。所有这些都会导致早产，每年影响1500万名婴儿，其中100万人死亡。在存活下来的婴儿中，十分之一会有残疾。因此，对胎盘植入方式的研究不仅有可能帮助女性怀孕，还可以通过避免婴儿过早出生来改善婴儿的健康。子宫内壁含有丰富的免疫细胞，称为“子宫自然杀伤细胞”，或称“Unk”。这些细胞被认为有助于胎盘植入，但我们还不知道是如何做到的。我们最近还发现Unk有三种类型：“uNK1”、“uNK2”和“uNK3”。每一个都可能有不同的作用，也许只有一个对胎盘植入至关重要。我想找出哪个子宫NK细胞亚群介导胎盘植入，以及它是如何实现的。为此，我将查看前来医院安装避孕圈的生育妇女的子宫衬里样本，并与前往我们生育诊所的妇女进行比较，这些妇女要么是因为两次以上流产，要么是因为试管受精后两次以上的植入失败。我将使用一种名为“流式细胞术”的技术，一次一个地观察我的参与者的细胞，找出每个细胞有多少，以及它们有多活跃。如果在胎盘植入有问题的女性中，有一个特定的亚群数量较少或活动较少，这将表明这些细胞对植入很重要。为了支持我的临床结论，我还将进行一些更密集的实验室工作。我将开发两种使用真实胎盘细胞的胎盘植入模型，一种在微芯片中，另一种在培养皿中。然后，我将看到添加每个Unk亚集的纯制剂如何改变这两个模型中胎盘细胞的行为方式：当我添加对植入重要的子集时，它将促进胎盘细胞的生长和迁移。我将使用这些植入模型来帮助我了解Unk是如何帮助胎盘植入的。例如，我可以阻止Unk制造的某些分子的作用：如果这些分子对着床很重要，阻止它们会使胎盘细胞生长和移动得不太好。相反，如果我加入更多的这些分子，它们对植入很重要，它们将促进胎盘细胞的生长和迁移。进行这些实验将使我能够识别哪些Unk亚群在以胎盘植入不良为特征的临床条件下不能正常工作，并在两个植入的实验室模型中证实我的发现。我还将使用这些模型来开始识别Unk制造的有助于促进植入的分子。这将是开发诊断工具的重要第一步，以确定哪些女性可能因植入不足而患上妊娠障碍，甚至可能推广能够促进胎盘植入的干预措施，最终减轻与植入不足相关的早产负担。