Computational modelling to evaluate, understand and predict the placental transfer of xenobiotics as an integrated system

在怀孕期间，子宫中的婴儿可能会接触到母亲正在服用的药物和她可能接触到的其他有毒物质。这些药物和毒药通过胎盘从母亲转移到婴儿身上，胎盘是将子宫中的婴儿通过脐带连接到母亲的器官。目前，关于某些物质如何穿过胎盘以及穿越到什么程度，存在很大的不确定性。这种信息的缺乏导致孕妇服用潜在不安全的药物，或者相反，导致建议避免使用让母亲变得更好的药物，而实际上这并不是必要的。为了解决这些问题，我们必须更好地了解胎盘是如何工作的。胎盘的转移非常复杂，因此在这个项目中，我们建议使用计算机模拟来更好地了解药物和有毒物质如何穿过胎盘。在胎盘中，来自母亲的血液和来自脐带的婴儿的血液不会混合，而是由特殊的屏障膜保持分离。这些胎盘膜含有特定的转运蛋白分子，可以将某些物质(例如婴儿所需的营养物质)带过体外，同时排除其他物质。转运蛋白也可以发挥积极作用，使胎盘通过排出有害物质来保护胎儿。虽然我们了解运输蛋白是如何单独工作的，但我们现在需要了解它们是如何协同工作的，这就需要我们的计算机模拟。我们将使用实验室实验，在多孔过滤器上培养胎盘细胞，以形成屏障层。然后我们将在许多不同的情况下进行实验，看看有多少被转移到膜上，然后使用我们的计算机模拟来计算出所有的膜转运体都在做什么。然后，我们将把这些结果与所谓的“芯片胎盘”进行比较，这是一个小型实验室系统，我们在其中模拟胎盘中血液流动的影响。最后，我们将把真正的胎盘(出生后捐赠)带入实验室，并在母体和胎儿一侧用泵将它们连接起来。这将使我们能够研究药物的转移，而不会危及婴儿。然后，我们可以精确地测试我们的计算机模拟是否能够准确地预测真实胎盘中发生的事情。通过这种方式将计算机模拟和实验相结合，我们将能够更好地了解胎盘是如何工作的，以及药物和有毒物质在多大程度上从母亲进入子宫中的婴儿。

During pregnancy the baby in the womb can be exposed to medicines the mother is taking and other poisonous substances she might be exposed to. These drugs and poisons are transferred from the mother to the baby via the placenta, which is the organ that connects the baby in the womb to the mother via the umbilical cord. There is currently a lot of uncertainty around exactly how certain substances cross the placenta and to what extent. This lack of information has resulted in pregnant mothers taking drugs that are potentially unsafe, or in contrast led to the advice to avoid drugs required to make the mother better when that was in fact not necessary. To address these issues it is essential that we understand better how the placenta works. Placental transfer is very complex, therefore in this project we propose to use computer simulations to understand better how substances such as drugs and poisonous substances cross the placenta.Within the placenta the blood from the mother and the baby's blood coming from the umbilical cord do not mix, instead they are kept separated by particular barrier membranes. These placental membranes contain specific transporter molecules that can take certain substances across (for example nutrients needed by the baby), while excluding others. Transporters can also play an active role, allowing the placenta to protect the fetus by pumping out harmful substances. Although we understand how transport proteins work in isolation, we now need to understand how they all work together, and that is where our computer simulations are needed.We will use laboratory experiments in which placental cells are grown on a porous filter to form a barrier layer. We will then do experiments with lots of different situations to see how much is being transferred across the membranes and then use our computer simulations to work out what all the membrane transporters were doing. We will then compare these results with those from the so called 'placenta-on-a-chip', which is a little laboratory system in which we mimic the effect of the blood flow in the placenta.Finally we will take real placentas (donated after birth) into the laboratory and connect them up with pumps on both the maternal and fetal side. This will allow us to study the transfer of medicines without endangering the baby. We can then test precisely if our computer simulations can accurately predict what is going on in the real placenta. By combining computer simulations and experiments in this way we will be able to understand better how the placenta works and to what extent drugs and poisonous substances go across from the mother to the baby in the womb.