Senior Research Associate
One-fifth of human pregnancies suffer from a variety of pregnancy disorders such as fetal growth restriction (FGR) and preeclampsia (PE), which threaten the lives of unborn babies and mothers as well as their wellbeing at adulthood and later life respectively. Despite decades of research, there are still no effective treatments available. The placenta is a transient organ that is vital for the success of a pregnancy. It forms the interface between the mother and her growing fetus, functioning like a "life-supporting machine" as well as shielding the fetus from maternal immune attack. Placental dysfunction is now well recognized to be central to many of pregnancy disorders, including miscarriage, FGR, stillbirth and PE. Placental oxidative stress and endoplasmic reticulum (ER) stress, which I recently identified, are at the root of etiology of these pathologies, but their pathophysiological roles are still unclear. My research interest is to explore and elucidate the molecular mechanisms behind oxidative and ER stress in modulating cellular responses under stressed conditions. Understanding their causative mechanisms will help in development of therapeutic intervention for the disorders.
Achievements so far:
1. I identified that placental ER stress is increased to different extents in a number of pregnancy disorders including FGR, early-onset PE, gestational diabetes, and small-for-gestational age at high altitude, but not in late-onset PE. The severity of placental ER stress shows a positive correlation with the degree of poor placentation and fetal growth restriction in these disorders.
2. PE is usually divided into early- and late-onset subtypes (before and after 34 weeks of gestation respectively because of its heterogeneity. My discovery of a different level of placental ER stress in these subtypes indicates its potential use as a molecular signature to define this classification.
3. I demonstrated that ER stress can modulate activity of AKT, which plays a central role in regulation of cell survival, growth and proliferation, through attenuation of protein translation as well as alteration of its downstream substrate specificity. These mechanisms likely contribute to the growth restriction phenotype in pregnancy disorders.
4. I have revealed that cells suffering chronic and low-grade ER stress secrete less bioactive proteins, possibly because of alteration in their glycosylation. This has a detrimental effect on the capacity of the placenta to modulate maternal physiology and metabolism towards pregnancy, and may impact adversely on resource allocation to the fetus.
5. In conjunction with Dr Mizuuchi, I demonstrated that placental ER stress regulates expression of the placental growth factor gene, thereby modulating maternal endothelial cell functions and contributing to the peripheral syndrome in PE.
Prof Abby Fowden, PDN, University of Cambridge, UK
Prof David Ron, Institute for Metabolic Science, University of Cambridge, UK
Prof Annetine Staff, University of Oslo, Norway
Prof Matt Olovsson, University of Uppsala, Sweden
Mizuuchi M, Cindrova-Davies T, Olovsson M, Charnock-Jones DS, Burton GJ, Yung HW, (2015), Placental endoplasmic reticulum stress negatively regulates transcription of placental growth factor via ATF4 and ATF6beta: implications for the pathophysiology of human pregnancy complications, J Path, Epub 2015/12/10
Matheson H, Veerbeek JH, Charnock-Jones DS, Burton GJ, Yung HW, (2015), Morphological and molecular changes in the murine placenta exposed to normobaric hypoxia throughout pregnancy, J Physiol, Epub 2015/08/19
Veerbeek JH, Tissot Van Patot MC, Burton GJ, Yung HW, (2015), Endoplasmic reticulum stress is induced in the human placenta during labour, Placenta, 36(1):88-92
Yung HW, Atkinson D, Campion-Smith T, Olovsson M, Charnock-Jones DS, Burton GJ, (2014), Differential activation of placental unfolded protein response pathways implies heterogeneity in causation of early- and late-onset pre-eclampsia, J Path, 234(2):262-76
Yung HW, Colleoni F, Atkinson D, Cook E, Murray AJ, Burton GJ, (2014), Influence of speed of sample processing on placental energetics and signalling pathways: implications for tissue collection, Placenta, 35(2):103-8
Yung HW, Hemberger M, Watson ED, Senner CE, Jones CP, Kaufman RJ, (2012), Endoplasmic reticulum stress disrupts placental morphogenesis: implications for human intrauterine growth restriction, J Path, 228(4):554-64
Yung HW, Cox M, Tissot van Patot M, Burton GJ, (2012), Evidence of endoplasmic reticulum stress and protein synthesis inhibition in the placenta of non-native women at high altitude, FASEB J, 26(5):1970-81
Jain A, Olovsson M, Burton GJ, Yung HW, (2012), Endothelin-1 induces endoplasmic reticulum stress by activating the PLC-IP(3) pathway: implications for placental pathophysiology in preeclampsia, Am J Path, 180(6):2309-20
Yung HW, Charnock-Jones DS, Burton GJ, (2011), Regulation of AKT phosphorylation at Ser473 and Thr308 by endoplasmic reticulum stress modulates substrate specificity in a severity dependent manner, PloS one, 6(3):e17894
Yung HW, Calabrese S, Hynx D, Hemmings BA, Cetin I, Charnock-Jones DS, (2008), Evidence of placental translation inhibition and endoplasmic reticulum stress in the etiology of human intrauterine growth restriction, Am J Path, 173(2):451-62
Yung HW, Korolchuk S, Tolkovsky AM, Charnock-Jones DS, Burton GJ, (2007), Endoplasmic reticulum stress exacerbates ischemia-reperfusion-induced apoptosis through attenuation of Akt protein synthesis in human choriocarcinoma cells, FASEB J, 21(3):872-84. E