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Graham Burton FMedSci

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Mary Marshall and Arthur Walton Professor of the Physiology of Repoduction
Tel: +44 (0)1223 333856, Fax: +44 (0)1223 333840, E-mail: gjb2@cam.ac.uk

Placental development and function

Research summary
My focus is on human early placental development, and the involvement of the placenta in complications of pregnancy such as miscarriage, intrauterine growth restriction and pre-eclampsia. In particular, we are interested in the effects of oxygen, hypoxia, and oxidative and endoplasmic reticulum stress on trophoblast differentiation and function at the molecular and cellular levels. By understanding these at the basic science level, we aim to develop novel therapeutic interventions to improve outcome in complicated pregnancies.

Key advances of the group
2000: Confirmed, in collaboration with Prof Eric Jauniaux, that the maternal arterial circulation to the placenta is not fully established in normal pregnancies until the end of the first trimester

2001: Proposed the concept of ischaemia-reperfusion injury to the placenta as the precipitating insult in the pathophysiology of early-onset pre-eclampsia

2002: Identified that the human conceptus is supported by histiotrophic nutrition from the endometrial glands during the first trimester of pregnancy

2003: Proposed concept that villous regression and remodelling at the end of the first trimester is induced by locally high levels of oxidative stress associated with onset of maternal blood flow

2004: Pioneered the application of stereological techniques to quantify the structure of the murine placenta

2005: Identified that phylogenetically old carbohydrate metabolic (polyol) pathways are highly active during the first trimester when the intraplacental oxygen concentration is low

2006: Demonstrated that fetal cell-free DNA is released from the placenta through apoptotic pathways

2007: Demonstrated that labour induces oxidative stress and transcriptional changes in the placenta that mimic those seen in pre-eclampsia

2008: First identification that endoplasmic reticulum stress contributes to the placental pathophysiology of intrauterine growth restriction

2009: Demonstrated that a proportion of the nuclei within the syncytiotrophoblast are transcriptionally active

2010: Identified a transcriptional network that may define a trophoblast stem cell population within the placenta

2011: Identified that soluble FLT1 sensitises endothelial cells to pro-inflammatory cytokines, a potential mechanism in pre-eclampsia

2012: First demonstration that endoplasmic reticulum stress compromises mitochondrial function through inhibition of synthesis of MTC complexes

2013: First demonstration that hydrogen sulphide is a potent placental vasodilator, and that production is impaired in pathological placentas with increased vascular resistance

Awards and honours
2001: International Spa Foundation Prize (with Prof E Jauniaux) for research on 'The role of placental oxygenation and generation of free radicals in the pathogenesis of miscarriages and preeclampsia'

2005: FEDERA Award from the Dutch Federation of Medical Scientific Societies for research on 'The maternal-fetal interface in early human pregnancy'

2007: Appointed inaugural Director of the Centre for Trophoblast Research (www.trophoblast.cam.ac.uk)

2008: Elected European Editor of Placenta

2011: Elected FMedSci

2013: Wim Schellekens Foundation Visiting Professor, Universities of Maastricht and Nijmegen

Colleagues
Professor Eric Jauniaux (University College Hospital, London)
Professor Stephen Charnock-Jones (University of Cambridge)
Professor Anne Ferguson-Smith (University of Cambridge)
Dr Myriam Hemberger
Dr Andrew Murray (University of Cambridge)
Professor John Kingdom (University of Toronto)
Dr Jeremy Skepper (University of Cambridge)
Dr Tereza Cindrova-Davies (Research Associate)
Dr Billy Yung (Research Associate)
Ms Norah Fogarty (Graduate Student)
Ms Melanie Monk (Research Technician)
Ms Nadine Law (Research Technician)

Funding
Wellcome Trust Programme grant, Anatomical Society, Action Medical Research, MRC, Evelyn Trust

Recent publications

Papers
Cindrova-Davies, T., Herrera, E.A., Niu, Y., Kingdom, J., Giussani, D.A. and Burton, G.J. (2013) Reduced cystathionine g-lyase and increased miR-21 are associated with increased vascular resistance in growth-restricted pregnancies: hydrogen sulfide as a placental vasodilator. Am J Pathol, 182, 1448-1458.

Yung, H.W., Hemberger, M., Watson, E.D., Senner, C.E., Jones, C.P., Kaufman, R.J., Charnock-Jones, D.S. and Burton, G.J. (2012) Endoplasmic reticulum stress disrupts placental morphogenesis: implications for human intrauterine growth restriction. J Pathol, 228, 554-564.

Hemberger, M., Udayashankar, R., Tesar, P., Moore, H. and Burton, G.J. (2010) ELF5-enforced transcriptional networks define an epigenetically regulated trophoblast stem cell compartment in the human placenta. Hum Mol Genetics, 19, 2456-2467.

Burton, G.J. (2009) Oxygen the Janus gas; its effects on human placental development and function .J Anat, 215, 27-35.

Burton, G.J., Woods, A.W., Jauniaux, E. and Kingdom, J.C.P. (2009) Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy. Placenta, 30, 473-482.

Books
Pathology of the Human Placenta. (2012) Benirschke, K., Burton, G.J. and Baergen, R., 6th edition. Springer, Berlin, pp. 941.

The Placenta and Human Developmental Programming. (2010) Eds. Burton, G.J., Barker, D.J.P., Moffett, A. and Thornburg, K. Cambridge University Press, Cambridge, pp. 246.

image

Above: Placental villi from a normal term placenta showing increased levels of oxidative stress following exposure to hypoxia-reoxygenation in vitro. The syncytiotrophoblast covering of the villi shows co-localisation (orange) of hydoxynonenal (green), a marker of lipid peroxidation, and the vasoconstrictor, endothelin (red). Nuclei are stained by DAPI (blue). Placental oxidative stress is thought to be a key mediator in the development of pre-eclampsia, stimulating the release of factors that cause maternal endothelial cell activation. Image courtesy of Dr Cindrova-Davies.


image

Above: The microvasculature of a terminal villus from a mature human placenta outlined by a fluorescent dye that binds to the fetal endothelial cells. Nuclei of the overlying syncytiotrophoblast are stained by DAPI (blue). The complex branching and localised dilations of the capillaries ensures efficient exchange between the maternal and fetal circulations. Image courtesy of Dr Skepper.