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Investigating placental nutrient transport in a mouse model of fetal growth restriction

Supervisor: Simon Tunster, Erica Watson

A modern epidemic of preventable chronic diseases such as obesity and type 2 diabetes is adversely affecting quality of life and ultimately placing an unsustainable burden on healthcare resources. Fetal growth restriction (FGR), which describes the failure of a fetus to achieve its genetic growth potential, is a known risk factor associated with developing these metabolic diseases in adulthood. However, the underlying mechanisms of this “fetal programming of adult disease” are poorly understood. Only by gaining a better understanding of the relationship between fetal growth and adult disease can we develop strategies aimed at preventing fetal programming in high-risk pregnancies.

Fetal growth is entirely dependent on the transport of sufficient nutrients across the placenta, with impaired placental function generally restricting fetal growth. In humans, elevated placental expression of PHLDA2 is frequently associated with FGR. In a mouse model of elevated Phlda2 expression, the placenta is smaller, with fetal growth restricted during late gestation. Whilst we know that both glycogen storage and endocrine function of these mutant placentae are substantially impaired, we have not yet investigated effects on nutrient transfer.

In vivo nutrient transport assays will be used to quantify placental nutrient transfer in this translationally relevant FGR model. In vitro techniques will be used to further explore the mechanisms associated with altered nutrient transfer, including stereological assessment of placental structure and quantitation of gene expression and protein abundance. These investigations will improve our understanding of the causal mechanism of FGR, which will inform the modification of maternal diets that will be tested to evaluate their efficacy at ameliorating growth restriction in this model.

Relevant references

Background on the model

S.J. Tunster, M. Van De Pette, R.M. John, Isolating the role of elevated Phlda2 in asymmetric late fetal growth restriction in mice, Dis Model Mech 7(10) (2014) 1185-91.

S.J. Tunster, H.D. Creeth, R.M. John, The imprinted Phlda2 gene modulates a major endocrine compartment of the placenta to regulate placental demands for maternal resources, Dev Biol  (2015).

Example of in vivo nutrient transfer assays

A.N. Sferruzzi-Perri, O.R. Vaughan, M. Haro, W.N. Cooper, B. Musial, M. Charalambous, D. Pestana, S. Ayyar, A.C. Ferguson-Smith, G.J. Burton, M. Constancia, A.L. Fowden, An obesogenic diet during mouse pregnancy modifies maternal nutrient partitioning and the fetal growth trajectory, FASEB J 27(10) (2013) 3928-37.

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