Perturbed expression of the Phlda2 gene as cause of placental dysfunction, intrauterine growth restriction and adult metabolic dysfunction
PhD Research
Funding:
The full studentship (fees and stipend) is available to UK or EU students who have been resident in the UK for at least three years. Other EU participants may receive a fees only award.
Applicants capable of self-funding (UK, EU and international) are also welcome to apply.
Project Description:
Primary Supervisor: Dr Rosalind John
Secondary Supervisor: Dr Nick Allen
Human infants that experience intrauterine growth restriction (IUGR) are 10-12 times more likely to die perinatally than normal-birth weight babies. Some are also doubly disadvantaged as they are particularly at risk of developing several diseases including type 2 diabetes, a phenomenon termed fetal programming. Expression of the imprinted gene, PHLDA2, is misregulated in a proportion of IUGR pregnancies (1). We have recently demonstrated a direct cause-and-effect relationship between high PHLDA2 expression and IUGR (2, 3). Growth restriction is late onset, asymmetric with a relative sparing of the neonatal brain and followed by rapid postnatal “catch-up”, a growth profile observed in human IUGR individuals that subsequently develop type 2 diabetes. Like their human counterparts, our transgenics become intolerant to glucose highlighting the potential role of epigenetic alterations in the earliest origins of adult disease.
The aims of this study are to
1. Perform a comprehensive survey of PHLDA2 expression in placentas collected at the University Hospital of Wales to determine the frequency of alteration in IUGR.
2. Assess the relative vulnerability of PHLDA2 to a number of interventional conditions such as altered maternal diet to identify the developmental origins of misregulated expression.
3. Determine which maternal diets accentuates or rescue growth restriction in a transgenic model.
This research will bring novel insights into the role of PHLDA2 in the developmental origins of health and disease and provide state-of-the-art training in genetics and the in vivo disease modeling of fetal programming of disease.
1 McMinn et al., (2006) Placenta, 27, 540-549.
2 Salas, et al., (2004) Mech Dev, 121, 1199-1210.
3 Tunster et al.,. (2010) Mol Cell Biol, 30, 295-306.