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

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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.