Research
Correct communication among fetus-placenta-mother is crucial for health pregnancy outcome and is largely orchestrated by placentally-derived proteins including hormones. I have previously demonstrated placental endoplasmic reticulum (ER) and mitochondrial stress playing central role in pathophysiology of preeclampsia, fetal growth restriction and gestation diabetes. Epidemiological studies reveal that both mother and her babies born from these complications are at increased risks of developing cardiometabolic diseases in their later life. Secretory and membrane proteins are synthesizing and folding in ER, while ER stress promotes protein misfolding. Can loss of placental signals predispose risk factors to fetus and mother? I have generated several transgenic models, such as junctional zone-specific ER stress (Jz-Perk-/-; Jz-Xbp1-/-) in which ER stress is activated exclusively in the placenta, promoting placenta secreting bio-inactive proteins. I have recently reported that loss of placental signals leads to maladaptation of maternal hepatic glucose metabolism. Next, I will use these transgenic animals to explore and elucidate molecular mechanisms for “programming” fetus and mother for the cardiometabolic diseases and whether alleviation of placental stress acts as therapeutic target.
Publications
1. O'Brien, K.A., Gu, W., Houck, J.A., Holzner, L.M.W., Yung, H.W., Armstrong, J.L., Sowton, A.P., Baxter, R., Darwin, P.M., Toledo-Jaldin, L., et al. (2024). Genomic Selection Signals in Andean Highlanders Reveal Adaptive Placental Metabolic Phenotypes That Are Disrupted in Preeclampsia. Hypertension 81, 319-329. 10.1161/HYPERTENSIONAHA.123.21748.
2. Yung, H.W., Zhao, X., Glover, L., Burrin, C., Pang, P.C., Jones, C.J.P., Gill, C., Duhig, K., Olovsson, M., Chappell, L.C., et al. (2023). Perturbation of placental protein glycosylation by endoplasmic reticulum stress promotes maladaptation of maternal hepatic glucose metabolism. iScience 26, 105911. 10.1016/j.isci.2022.105911.
3. Yung, H.W., Burton, G.J., and Charnock-Jones, D.S. (2023). Protocol for culturing the endocrine junctional zone of the mouse placenta in serum-free medium. STAR Protoc 4, 102384. 10.1016/j.xpro.2023.102384.
4. Capatina, N., Burton, G.J., and Yung, H.W. (2022). Elevated homocysteine activates unfolded protein responses and causes aberrant trophoblast differentiation and mouse blastocyst development. Physiol Rep 10, e15467. 10.14814/phy2.15467.
5. Capatina, N., Hemberger, M., Burton, G.J., Watson, E.D., and Yung, H.W. (2021). Excessive endoplasmic reticulum stress drives aberrant mouse trophoblast differentiation and placental development leading to pregnancy loss. J Physiol 599, 4153-4181. 10.1113/JP281994.
6. Burton, G.J., Cindrova-Davies, T., Yung, H.W., and Jauniaux, E. (2021). HYPOXIA AND REPRODUCTIVE HEALTH: Oxygen and development of the human placenta. Reproduction 161, F53-F65. 10.1530/REP-20-0153.
7. Blake, G.E.T., Zhao, X., Yung, H.W., Burton, G.J., Ferguson-Smith, A.C., Hamilton, R.S., and Watson, E.D. (2021). Defective folate metabolism causes germline epigenetic instability and distinguishes Hira as a phenotype inheritance biomarker. Nat Commun 12, 3714. 10.1038/s41467-021-24036-5.
8. Yung, H.W., Colleoni, F., Dommett, E., Cindrova-Davies, T., Kingdom, J., Murray, A.J., and Burton, G.J. (2019). Noncanonical mitochondrial unfolded protein response impairs placental oxidative phosphorylation in early-onset preeclampsia. Proc Natl Acad Sci U S A 116, 18109-18118. 10.1073/pnas.1907548116.
9. Lee, C.L., Veerbeek, J.H.W., Rana, T.K., van Rijn, B.B., Burton, G.J., and Yung, H.W. (2019). Role of Endoplasmic Reticulum Stress in Proinflammatory Cytokine-Mediated Inhibition of Trophoblast Invasion in Placenta-Related Complications of Pregnancy. Am J Pathol 189, 467-478. 10.1016/j.ajpath.2018.10.015.
