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Understanding the origins of syncytial nuclear aggregates – insights into their role in stillbirth.

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  • Full or part time
    Dr Heazell
    Prof Aplin
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

Placental dysfunction underpins important pregnancy complications, fetal growth restriction and pre-eclampsia that pose health risks to the mother and fetus, particularly stillbirth. Currently the precise causes of these diseases are unknown. These diseases are marked by the earlier arrival and increase in number of syncytial nuclear aggregates (SNAs) in the outer cell layer of the placenta. SNAs are also more evident in post-mature pregnancies.

Prior research by our and other groups has demonstrated that SNAs are increased in preeclampsia and fetal growth restriction but are not apoptotic as previously thought. We have demonstrated that SNAs are stable once formed and inhibition of cytoskeletal proteins does not interrupt their formation or cause their dissolution. We have used an in silico model to model potential sources of the formation of SNAs.

Our hypotheses are:
i. Nuclei in the syncytiotrophoblast may become more “sticky” by altered expression of nuclear envelope proteins such as SUN and KASH proteins.
ii. The site of nuclei entering the syncytium may affect how nuclei join SNAs.

We wish to develop our culture models to evaluate whether these mechanisms may be involved in SNA formation and how they relate to pathological conditions in the placenta. We anticipate that these insights into the formation of SNAs will increase our understanding of placental dysfunction in preeclampsia, fetal growth restriction and stillbirth.

The project will be conducted within the Maternal and Fetal Health Research Centre, the largest translational placental research group in Europe. The successful candidate will receive training in cell and tissue culture including histological assessment of placental morphology immunohistochemistry, Western blotting and laser capture microdissection.

Candidates would be expected to hold a minimum of an upper-second class (or equivalent) undergraduate degree with a background in reproductive biology. A Masters and insight into pregnancy complications would be advantageous.

This 4-year full-time PhD is open to candidates able to provide evidence of self-arranged funding/ sponsorship and is due to commence from January 2017 onwards.

Any enquiries relating to the project and/or suitability should be directed to Dr Heazell ([email protected]). Applications are invited on an on-going basis but early expression of interest is encouraged.

Funding Notes

This project has a Band 2 fee. Details of our different fee bands can be found on our website. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website. Informal enquiries may be made directly to the primary supervisor.

References

1. IFPA Gábor Than Award Lecture: Recognition of placental failure is key to saving babies' lives. Heazell AE, Worton SA, Higgins LE, Ingram E, Johnstone ED, Jones RL, Sibley CP. Placenta. 2015 Apr;36 Suppl 1:S20-8.
2. Systematic review of placental pathology reported in association with stillbirth. Ptacek I, Sebire NJ, Man JA, Brownbill P, Heazell AE. Placenta. 2014 Aug;35(8):552-62.
3. Analysis of syncytial nuclear aggregates in preeclampsia shows increased sectioning artefacts and decreased inter-villous bridges compared to healthy placentas. Calvert SJ, Jones CJ, Sibley CP, Aplin JD, Heazell AE. Placenta. 2013 Dec;34(12):1251-4.
4. Syncytial nuclear aggregates in normal placenta show increased nuclear condensation, but apoptosis and cytoskeletal redistribution are uncommon. Coleman SJ, Gerza L, Jones CJ, Sibley CP, Aplin JD, Heazell AE. Placenta. 2013 May;34(5):449-55.
5. Syncytial knots (Tenney-Parker changes) in the human placenta: evidence of loss of transcriptional activity and oxidative damage. Fogarty NM, Ferguson-Smith AC, Burton GJ. Am J Pathol. 2013;183(1):144-52.

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FTE Category A staff submitted: 136.18

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