Supervisors: Professor Graham J Burton and Dr HW Yung
Maternal endothelial dysfunction is one of the hallmarks of preeclampsia, resulting in hypertension, edema, and proteinuria. However, the role of placenta in the endothelial cell activation is far from clear, especially in early-onset preeclampsia when there is severe placental pathology. The placenta secretes a vast quantity of hormones, growth factors and biomolecules into the maternal circulation, thereby modulating maternal physiology to sustain pregnancy. The high endocrine activity of placenta makes its highly susceptible to endoplasmic reticulum (ER) stress, which is a physiological stress response mechanism controlling the quality of newly synthesized secreted proteins. We have demonstrated that, cells secrete anomalous glycosylated proteins in response to chronic ER stress (Yung et al. 2012), and that ER stress is present in placentas of complicated pregnancies, such as early-onset pre-eclampsia (Yung et al. 2008, Yung et al. 2014). Glycosylation of secreted proteins is an essential determinate of their antigenicity, circulating half-life, and bioactivity. Therefore, we hypothesize that in pre-eclampsia, under ER stress, the placenta may release anomalously glycosylated proteins into the maternal circulation, thereby causing maternal endothelial cell dysfunction and systemic inflammation. In this project, you will first test whether proteins secreted by ER stressed cells provoke immune responses and adversely affect the function of endothelial cells in vitro. Later, you will explore this effect further in in vivo systems using a transgenic animal model in which ER stress is induced specifically in the endocrine region of the placenta. The impact on immune and endothelial cell functions will be assessed throughout pregnancy. The results will provide new insights into the pathophysiology of this common and potentially devastating condition.
Yung, H. W., D. Atkinson, T. Campion-Smith, M. Olovsson, D. S. Charnock-Jones and G. J. Burton (2014). "Differential Activation of Placental Unfolded Protein Response Pathways Implies Heterogeneity in Causation of Early- and Late-onset Pre-eclampsia." J Pathol 234: 262-276.
Yung, H. W., S. Calabrese, D. Hynx, B. A. Hemmings, I. Cetin, D. S. Charnock-Jones and G. J. Burton (2008). "Evidence of placental translation inhibition and endoplasmic reticulum stress in the etiology of human intrauterine growth restriction." Am J Pathol 173: 451-462.
Yung, H. W., M. Hemberger, E. D. Watson, C. E. Senner, C. P. Jones, R. J. Kaufman, D. S. Charnock-Jones and G. J. Burton (2012). "Endoplasmic reticulum stress disrupts placental morphogenesis: implications for human intrauterine growth restriction." J Pathol 228: 554-564.
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