Fetal Growth Restriction: A Failure of Placental Adaptation In Response To Fetal Nutrient Demand?

Babies that are born small (they fail to reach the size their genetics would suggest) are at greater risk of being stillborn. Should these babies survive, they are then at a greater risk of disability in childhood (e.g. cerebral palsy, developmental delay). There are now well defined links between being born small, termed Fetal Growth Restriction (FGR), and an increased risk of adulthood diseases such as high blood pressure (and subsequent risk of heart attack) or diabetes. Thus, FGR is responsible for a significant emotional and financial burden on families and the NHS, both before and after birth. Despite this, there are no new drugs currently being designed specifically for use in pregnancy-related diseases such as FGR.
For growth of the baby to proceed as normal, a placenta that functions as normal is crucial. The placenta supplies oxygen and other nutrients to the growing baby and eliminates waste products via mother. When the placenta fails to function as normal, FGR may ensue. Despite it being acknowledged that a poorly functioning placenta may result in FGR, the mechanisms behind this are still not well understood. Most research thus far has focused on how signals from mother are able to cause changes in how the placenta transfers nutrients to the mother and how this is altered in FGR. This study aims to examine the signals that baby produces in more detail. Evidence suggests that in normal pregnancy, baby is able to signal to mother to alter the amount of nutrients getting across, via the placenta, to baby. This helps baby's growth to proceed as normal. In FGR, there is evidence that this signaling between baby and mother fails; thus the transfer of nutrients by the placenta is insufficient for normal growth and FGR occurs. This study shall assess human placentas from both normal and FGR-affected pregnancies to assess what these important fetal signals may be. This includes the use of cutting-edge technologies to identify key markers within umbilical artery blood (which flows from the baby back to the placenta) and the fetal-facing side of the placenta (where these signals would bind). Important signals would then be administered to the placenta after delivery of the baby (in a system that mirrors pregnancy). This would examine whether these signals altered placental transfer of nutrients in a manner that would be beneficial for baby.
This study will shed new light onto how baby is able to signal back to mother and how these signals cause changes in the delivery of nutrients back to baby by the placenta. This information will allow exploitation of these signals with an ultimate aim of improving baby's growth in at-risk pregnancies. This work will take place within the Maternal and Fetal Health Research Centre (MFHRC), University of Manchester. The MFHRC is the largest pregnancy-based research group in Europe and has a deserved reputation as a world-class research facility. The MFHRC consists of scientists, clinicans and midwives, all of whom work together with a combined aim of making pregnancy safer for both mum and baby.

Fetal growth restriction (FGR), the inability of a fetus to achieve its genetic growth potential, is a major clinical problem. FGR significantly increases the risk of stillbirth and childhood morbidity, whilst being born `small' increases the risk of diseases such as hypertension in adulthood. Whilst placental dysfunction is known to be a major causative factor in FGR, there are multiple aetiologies, many of which are still poorly understood. In normal pregnancy, there is evidence that placentas of differing size alter their nutrient supply capacity, to maintain normal fetal growth. In FGR, this adaptation appears to fail. I hypothesise that in pregnancies leading to appropriate growth of the fetus, there are fetal signals that adapt placental nutrient transfer capacity in order for the fetus to achieve its genetic growth potential. I also hypothesise that in FGR, fetuses either no longer produce these signals or the placenta is unable to respond to fetal signals. This study aims to test these hypotheses and determine the identity of some of the fetal signals that adapt nutrient transfer in normal pregnancies and whether these signals are lacking in FGR pregnancies. In order to meet the aims, metabolomic analysis will be carried out on blood collected from umbilical arteries together with proteomic analysis of placental tissue. This will enable the identification of candidate fetal signals that drive alterations in placental nutrient transport. In addition, candidate fetal signals will be administered specifically on the fetal side of the normal or FGR placenta in an ex-vivo perfused placenta model and their effect on maternofetal nutrient (calcium, amino acid) transport measured. Human studies will be complemented with work on mouse genetic models of abnormal fetal growth.This study will provide the first comprehensive profile of candidate fetal signals that drive placental adaptation and whether these are altered in FGR.

Since insufficient transport of nutrients has been identified as a causative factor in the development of fetal growth restriction (FGR), approaches to rectify this clearly present an attractive therapeutic strategy in the future. Growing evidence suggests that in normal pregnancies, the fetus is able to 'detect' when nutrient supply is inadequate and thus signal back to the placenta to normalize maternofetal nutrient transfer across the placenta, thus maintaining normal growth. Two hugely important questions remain; (i) what are these signals and (ii) are these absent in FGR or is it the placenta that is no longer able to respond to these signals? By the end of this 5-year Fellowship, a small, but specific, list of candidate fetal signals will have been drawn up. In addition, it will be known whether these specific signals are lacking in FGR or if the pathologies of FGR placentas prevent a response to these signals from occurring.
These data will be of interest to pharmaceutical companies; candidate fetal signals that are lacking in FGR would provide a direct therapeutic target in FGR pregnancies. Even though these signals are targeted to the fetal facing basal plasma membrane (BM) of the placental syncytiotrophoblast (transporting epithelium), an increase in maternofetal nutrient transport may also be observed following administration into the mother. Also, studies exist in our group that are looking at novel-targeting peptides that permit delivery of a drug to a specific target within the body. This would allow signals to be delivered specifically to the syncytiotrophoblast (and ideally the BM) thus preventing adverse outcomes in the fetus. This is achievable within 5-10 years.
To facilitate translation of this basic scientific research into an effective biotechnological application, the University of Manchester runs a system for the early filing of patents on exploitable findings, and the Research to Enterprise Centre aids researchers with business plans and marketing strategies, and interfaces with the commercial sector (http://www.rte.manchester.ac.uk/). These resources will provide me with the support and guidance to effectively exploit my research. In addition, scientists and clinicians within The Maternal and Fetal Health Research group have worked closely with pharmaceutical companies including Pfizer and Ardana Biosciences in the past, thus I will capitalize on these existing links at an appropriate time.