Amino acid transport through the placenta: an experimental and modelling investigation

While in the womb the baby obtains all the nutrients it requires for growth and development from the placenta. This organ transfers nutrients from maternal blood to the baby's blood. If the placenta does not transfer enough nutrients, the fetus will not be able to grow adequately and may be born too small. Babies who are born too small are more likely to develop health problems, both in early life and in adulthood. To understand the normal processes by which babies grow in the womb and to understand why this process is sometimes disturbed, we need to fully appreciate how nutrients are transported across the placenta. Understanding normal placental function will allow us to define what might go wrong when growth of the baby becomes impaired and how this might be prevented or treated at an early stage. In this project we will develop a computer model of how the placenta functions which can be used to better understand how the placenta works normally and also how it can go wrong in a difficult pregnancy. We are particularly interested in the placental transfer of amino acids. These are the building blocks of proteins which form muscles and the cellular 'machinery' essential for life. Thus, amino acids are an important class of nutrients, and their placental transfer is essential for optimal growth of the baby in the womb. In pregnancies where the baby was born small, placental amino acid transport has been shown to be lower than in babies of normal birth weight. Placental amino acid transfer is a complex process which is dependent on (i) amino acid transporters - (carriers) which take nutrients from maternal blood and release them into fetal blood, (ii) on blood flow through the placenta, (iii) on the internal structure of the placenta, and (iv) on the levels of amino acids in maternal and fetal blood as well as inside the cells which make up the placenta. The way these factors affect amino acid transfer cannot be understood in isolation as there are complicated interdependent interactions between them. Therefore, developing a computer model of these complex interactions will allow us to study how the placenta works as an integrated system. We have already designed a simple model that simulates the function of amino acid transporters in the human placenta and which can predict the transport of up to 3 amino acids at any one time. We have tested this model by comparing it to what we observe experimentally in placentas collected immediately after birth. These tests show that the model can convincingly reproduce experimental data, but we now need to expand our system to accurately simulate the simultaneous transport of the entire set of 20 amino acids. Such a model must incorporate other influences on placental transport such as the internal structure and blood flow patterns of the placenta. Ultimately, a well validated virtual placental amino acid transport model will help to explain how the components of the normal placenta function to transport amino acids to the baby and sustain optimal growth. It will identify the most important factors which affect placental amino acid transport and will allow future studies to be focused on such factors that are likely to have the greatest impact, leading to the development of effective strategies to ensure babies grow optimally in the womb. These strategies may include algorithms to predict how mothers metabolic state may affect placental amino acid transport (e.g. in maternal diabetes, teenage pregnancy) and to develop personalised interventions or using the model to identify key targets for pharmacological interventions. Ultimately we intend that this work will contribute to the development of a fully-fledged Virtual Placenta, one that does not just model amino acid transport but all the placental functions.

Placental amino acid transfer is essential to sustain fetal growth. Many factors influence this process and the complexity of the system makes it difficult to determine their relative importance. The aim of this project is to exploit mathematical modelling of placental amino acid transfer to gain insight into how the different factors interact and identify key rate-limiting steps for amino acid transfer. Placental transfer of amino acids is mediated by at least 12 transport proteins, differentially localised to the microvillus maternal facing plasma membrane and basal fetal facing plasma membrane of the placental syncytiotrophoblast. Transfer of amino acids requires complex interactions between different classes of transporters on both membranes. These interactions mean that transfer of an amino acid may depend on transporters for which it is not a substrate. Transporter activity is dependent on substrate concentrations which, in turn, are dependent on both maternal and fetal arterial concentrations as well as maternal and fetal blood flow. Total placental exchange capacity will also be dependent on the surface area of the placenta available for transport and on transporter density. Finally some amino acid transfer across the placenta will occur by diffusion so that the passive permeability of the placenta must also be included. The complex nature of this system means that understanding each of its components in isolation does not allow intuitive prediction of how the system works as a whole. A mathematical model of the placenta will allow the interaction of its components to be investigated and understood as an integrated system. The development of a mathematical virtual placental amino acid transport model will allow us to dissect the rate-limiting steps in amino acid transport as well as how the placenta functions as a whole. This will enable future studies of potential key targets for manipulation and therapy.

This research will have significant impact in academic terms and also has the potential to have considerable impact in economic and social sectors. The immediate outcomes of this work, most notably an improved understanding of how the placenta functions as an integrated system, will be of great academic interest and will ultimately translate into improvements in clinical care and obstetric practice. Growth of the baby in the womb has important implications for lifelong health (a BBSRC priority) and advances which help ensure optimal placental nutrient transfer and fetal growth will potentially lead to improved long term health throughout the general population. From a mathematical perspective, amino acid transport in the placenta offers a highly complex, coupled nonlinear system displaying nontrivial behavior which cannot be predicted intuitively beforehand. Key aspects of this work including the action of amino acid transporters, the interaction of structure, flow and transport will be applicable to modeling other biological systems in humans and animals. Tools and methods developed for this project should find applications across a wide range of biological systems where spatial temporal transport across thin membranes is critical. These might include transport of nutrients across the epithelium of the small intestine, the renal tubular epithelium and the blood brain barrier. The academic impact of this work will come from the intellectual advances made by the work, the skills developed by both staff and applicants and the contribution to the UK's developing excellence in the area of placental modelling. The training of highly skilled researchers and the experience it will provide for systems biologists, mathematicians and engineers to work in an interdisciplinary team. The innovative models developed by this project will have application not only for placental function but will be readily applicable to the study of transepithelial nutrient transport in other systems and other species. Through interactions with other researchers in the UK this project will enhance the UK's developing excellence in placental modelling. The outcomes of this research will constitute a significant advance in our understanding of placental biology and in the development of innovative approaches to mathematical modelling of complex systems. These findings will be communicated nationally and internationally through presentation at conferences and publication in high impact peer reviewed journals. As such this work will make a significant contribution to worldwide academic advancement and the UK's capacity to undertake research in these and related areas. The economic and societal impacts of this work will come through the application of the findings of this work to the health of women and their children, to life long health and through commercial application. Poor fetal growth increases an individual's risk of developing chronic disease, such as heart disease or diabetes, in adult life. This is a significant burden to the individuals themselves, to the NHS, workplaces and society as a whole. Furthermore, poor adult health in women may affect the development and subsequent health of their offspring thus creating a cycle of sustained ill-health throughout the population across generations. By improving our understanding of placental biology and identifying those factors which are most important determinants of placental amino acid transport this work will enable future studies to target these factors. This will allow more focused allocation of future research funding and may also reduce the need for animal experiments. This work may have commercial impact directly thorough consultancies, licensing and spin out companies and through the contribution of this research to the knowledge economy. Its impact will not be restricted to the placenta but may have application in many other human systems such as intestinal renal and liver function.