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

作为一个综合系统评估、理解和预测异生素胎盘转移的计算模型

基本信息

批准号：
BB/R002762/1
负责人：
Bram Gijsbert Sengers
金额：
$ 53.74万
依托单位：
University of Southampton
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FR002762%2F1
关键词：
Computational modelling evaluate understand predict

项目摘要

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.

在怀孕期间，子宫内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。这些药物和毒素通过胎盘从母亲转移到婴儿身上，胎盘是通过脐带将子宫中的婴儿与母亲联系起来的器官。目前，关于某些物质如何穿过胎盘以及在多大程度上穿过胎盘还存在很多不确定性。这种信息的缺乏导致孕妇服用可能不安全的药物，或者相反，导致建议避免使用实际上不必要的药物来使母亲更好。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血液不会混合，而是通过特殊的屏障膜保持分离。这些胎盘膜含有特定的转运分子，可以携带某些物质（例如婴儿所需的营养素），同时排除其他物质。转运蛋白也可以发挥积极作用，使胎盘通过泵出有害物质来保护胎儿。虽然我们已经了解了转运蛋白是如何单独工作的，但我们现在需要了解它们是如何一起工作的，这就是我们需要计算机模拟的地方。我们将使用实验室实验，在实验中胎盘细胞生长在多孔过滤器上，形成一个屏障层。然后，我们将在许多不同的情况下做实验，看看有多少东西穿过膜，然后用我们的计算机模拟来计算所有膜转运蛋白的作用。然后，我们将这些结果与所谓的“胎盘芯片”的结果进行比较。“胎盘芯片"是一种小型实验室系统，我们在其中模拟胎盘中的血流效果。最后，我们将把真实的胎盘（出生后捐赠的）带到实验室，并将它们与母体和胎儿侧的泵连接起来。这将使我们能够在不危及婴儿的情况下研究药物的转移。然后我们可以精确地测试我们的计算机模拟是否可以准确地预测真实的胎盘中发生的事情。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如何工作，以及药物和有毒物质在多大程度上从母亲传递到子宫中的婴儿。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Glibenclamide transfer across the perfused human placenta is determined by albumin binding not transporter activity.

格列本脲跨灌注人胎盘的转移是由白蛋白结合而不是转运蛋白活性决定的。

DOI：
10.1016/j.ejps.2020.105436
发表时间：
2020
期刊：
official journal of the European Federation for Pharmaceutical Sciences
影响因子：
0
作者：
Lofthouse EM
通讯作者：
Lofthouse EM

Estrone sulphate uptake by the microvillous membrane of placental syncytiotrophoblast is coupled to glutamate efflux.

DOI：
10.1016/j.bbrc.2018.10.074
发表时间：
2018-11-17
期刊：
Biochemical and biophysical research communications
影响因子：
3.1
作者：
Lofthouse EM;Cleal JK;O'Kelly IM;Sengers BG;Lewis RM
通讯作者：
Lewis RM

3D visualization of trans-syncytial nanopores provides a pathway for paracellular diffusion across the human placental syncytiotrophoblast.

DOI：
10.1016/j.isci.2022.105453
发表时间：
2022-12-22
期刊：
ISCIENCE
影响因子：
5.8
作者：
Lewis, Rohan M.;Baskaran, Harikesan;Green, Jools;Tashev, Stanimir;Palaiologou, Eleni;Lofthouse, Emma M.;Cleal, Jane K.;Page, Anton;Chatelet, David S.;Goggin, Patricia;Sengers, Bram G.
通讯作者：
Sengers, Bram G.

Computational Modelling of Paracellular Diffusion and OCT3 Mediated Transport of Metformin in the Perfused Human Placenta