Investigating a novel molecular diagnostic tool for identification and stratification of pregnancy complications

在子宫内生长不良的婴儿，被称为小于胎龄（SGA），对母亲和婴儿的健康问题的风险都在增加。例如，体重过轻的足月婴儿的新生儿死亡风险比体重正常的足月婴儿高30倍。对孕妇进行筛查，试图发现SGA婴儿，有可能减少这些不良后果的数量——英国每年死于死胎和新生儿问题的婴儿总数超过5000名。目前很难监测胎儿在子宫内的生长情况，更难预测是否会出现与此相关的健康问题。虽然有许多针对SGA婴儿的扫描和血液标记物，但这些标记物本身都不足以预测他们。我们最近发现，通过测量母亲血液中一种叫做DLK1的蛋白质，我们可以提高对婴儿是否会小的预测。在第一项研究中，我们只检查了一小部分孕妇，但数据表明，DLK1水平异常与无法形成有效胎盘有关。胎盘是一个临时器官，从母亲的血液中为婴儿提供营养和氧气，并清除废物。许多妊娠并发症被认为是由于胎盘发育不正常而发生的。然而，对于健康的胎盘需要哪些基因，以及如果基因突变，这是如何出错的，我们还有很多需要发现的。有趣的是，DLK1是在胎盘中产生的。当我们研究DLK1基因突变的小鼠时，我们发现它们的胎盘更小，母体和胎儿血液之间的营养和氧气交换区域也减少了。然而，我们目前还不明白为什么制造一个健康的胎盘需要DLK1。这个项目的目的首先是看看在大量孕妇的血液中测量DLK1如何帮助我们提高对小婴儿的预测。我们可以获得扫描信息、血液样本和胎盘样本，这些样本来自于一项大规模的研究，研究对象是未被选中的首次怀孕的女性（约3000名）。目前应用的首要目标是看看我们是否能在发育不良婴儿的母亲血液中找到更好的标记物，并进一步将DLK1的水平与胎盘问题联系起来。其次，因为我们有没有工作的DLK1基因的小鼠，我们可以研究它们，以了解制造健康胎盘所需的过程。我们将利用研究小鼠产生的新想法来设计使用人类胎盘样本的实验，以测试我们的发现是否有助于理解为什么人类胎盘会出错。

Babies who grow poorly in the womb, called small for gestational age (SGA), are at increased risk of health problems for both mother and baby. For example, full-term infants who are SGA have up to 30 times higher risk of neonatal death compared to term infants born at average weight. Screening pregnant women in an attempt to detect SGA babies has the potential to reduce the number of these adverse outcomes -the combined deaths from stillbirth and neonatal problems exceed 5000 babies every year in the UK. Currently it is difficult to monitor growth of the baby in the womb, and even harder to predict if there will be health problems associated with this. While there are a number of scan and blood markers for SGA babies, none of these is good enough on its own to predict them. We have recently found that by measuring a protein called DLK1 in the mother's blood we can improve the prediction of whether the baby will be small. In this first study we examined only a small selection of pregnant women, but the data suggested that abnormal DLK1 levels were associated with failure to make an efficient placenta. The placenta is a temporary organ that is necessary for providing nutrition and oxygen to the baby from the mother's blood, and for removing waste. Many of the complications of pregnancy are thought to occur because the placenta does not develop properly. However, we still have much to discover about which genes are needed to make a healthy placenta, and how this goes wrong if the genes are mutated. Interestingly, DLK1 is made in the placenta. When we studied mice with a mutated DLK1 gene we found that they had smaller placentas and a reduced area for nutrient and oxygen exchange between the maternal and fetal blood. However, we currently don't understand why DLK1 is required to make a healthy placenta. The aim of this project is firstly to see how measuring DLK1 in the blood of a large number of pregnant women can help us improve prediction of small babies. We have access to scan information, blood samples and placental samples from a large scale study of unselected women in their first pregnancy (~3000 women). The overarching aim of the present application is to see if we can find better markers in the mother's blood of poorly grown babies, and further link the levels of DLK1 to problems with the placenta. Secondly, because we have mice without a working DLK1 gene, we can study them to understand the processes necessary to make a healthy placenta. We will use the new ideas generated by studying the mice to design experiments using the human placental samples to test if our findings can help to understand why placentation goes wrong in humans.