Our projects: Fetal programming of the cell cycle

In 2008 we received funding from the BBSRC (PI Simon Langley-Evans, CoI Sarah McMullen, Harry McArdle, Lorraine Gambling) to carry out what we called the Gatekeeper Study. This aimed to examine the effects of maternal protein restriction and iron deficiency in rat pregnancy upon the whole embryonic transcriptome and proteome in order to identify common genes, pathways and proteins that were differentially regulated in common with the two insults. The hypothesis was that these common (gatekeeper) targets must play a critical role in linking maternal undernutrition to the renal and cardiovascular phenotypes associated with the two insults. The principal of this is set out in our review in Medical Hypotheses.

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Our findings, as described in two PlosOne articles, showed that regulation of the cell cycle was disturbed by both protein restriction and iron deficiency and this finding was subsequently verified in a study of the neonatal hepatic transcriptome (in collaboration with Adrian Clark and Elia Stupka). Maternal undernutrition impacts upon expression of several of the cyclins (A2, B, H and E), genes which regulate DNA replication and genes that are involved in the G1/S and G2/M checkpoints. Our working hypothesis is that disruption of cell cycle regulation during embryonic and fetal life impacts upon the development of organs and tissues, resulting in tissue remodelling and irreversible loss of functional capacity.

This work is currently proceeding as an MRes studentship (Alice Cordon) which will examine expression of key gene and protein targets in a range of tissues from offspring of protein restricted pregnancies at different ages. It is likely that transient changes in expression is sufficient to perturb tissue development and that the transcriptome will not show permanent consequences of maternal dietary exposure.

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