Graduate Research Prize Winner 2015
I completed my BSc and MSc degrees in the Natural Sciences at The National Chung Hsin University and The National Taiwan University, respectively. As a part of my undergraduate research, I investigated plant virus-host interactions with Professor Shyi-Dong Yeh. I developed a further interest in biochemistry during my Masters degree, where I studied isoprenoid biosynthesis with Professors Po-Huang Liang & Andrew H.-J Wang and Vaccinia virus infection with Professors Andrew H.-J. Wang and Wen Chang at The Academia Sinica, Taiwan. These research experiences were fascinating and inspired me to pursue a DPhil focused on understanding disease pathways using techniques in molecular and structural biology.
In 2010, I was awarded a Prize studentship from the Nuffield Department of Clinical Medicine with scholarships from the Clarendon Foundation and Somerville College. Supervised by Professor Yvonne Jones in the Division of Structural Biology (STRUBI), I investigated the structural basis for how ligand and receptor genetic mutations in human Wnt signalling pathways can lead to inherited retinal diseases such as: Norrie Disease, Familial Exudative Vitreoretinopathy and Coats’ disease. Wnt proteins play an essential role in cell-fate determination, tissue homeostasis and embryonic development.
During my project, I elucidated how Norrin (Norrie Disease Protein) can act as a molecular mimic to Wnt and interact with Wnt receptors: Frizzled 4, low-density lipoprotein receptor related protein 5/6, and heparan sulphate proteoglycans. These results provided important insights into the mechanism by which Wnt signalling pathways are activated and enabled us to map numerous disease-associated mutations onto the Norrin protein and its receptors.
One of major achievements during my project was the development of a novel and efficient recombinant protein expression and purification strategy for the Norrin protein. Norrin initially proved very difficult to produce in useful amounts. This new methodology is currently being adopted for continued research and collaborations within STRUBI and is also being used in the development of new treatments for ophthalmic diseases, cancers, and regenerative medicines by Ximbio, Cancer Research Technology, London. In the final year of my DPhil, I was awarded one of two best student presentation prizes in the EMBO workshop- Wnt signalling: stem cells, development and disease (Broom, Australia).
My DPhil studies have benefited from working with excellent colleagues as well as having a supportive supervisor. Throughout my time in Oxford, I feel very lucky to have had the full support from my wife, Fu-Lien Hsieh. I am extremely grateful for her inspiration and optimistic attitude and would like to dedicate this award to Fu-Lien.
Chang, T.H., Hsieh, F.L., Zebisch, M., Harlos, K., Elegheert, J., and Jones, E.Y. (2015). Structure and functional properties of Norrin mimic Wnt for signalling with Frizzled4, Lrp5/6, and proteoglycan. Elife 4, e06554.
Kakugawa, S.*, Langton, P.F.*, Zebisch, M.*, Howell, S.A., Chang, T.H., Liu, Y., Feizi, T., Bineva, G., O'Reilly, N., Snijders, A.P., Jones, E.Y., and Vincent, J.P. (2015). Notum deacylates Wnt proteins to suppress signalling activity. Nature 519, 187-192. * Equal contribution
Chang, C.K., Teng, K.H., Lin, S.W., Chang, T.H., and Liang, P.H. (2013). Control activity of yeast geranylgeranyl diphosphate synthase from dimer interface through H-bonds and hydrophobic interaction. Biochemistry 52, 2783-2792.
Chang, T.H.*, Chang, S.J.*, Hsieh, F.L., Ko, T.P., Lin, C.T., Ho, M.R., Wang, I., Hsu, S.T., Guo, R.T., Chang, W., and Wang, A.H. (2013). Crystal structure of vaccinia viral A27 protein reveals a novel structure critical for its function and complex formation with A26 protein. PLoS pathogens 9, e1003563. * Equal contribution
Hsieh, F.L.*, Chang, T.H.*, Ko, T.P., and Wang, A.H. (2011). Structure and mechanism of an Arabidopsis medium/long-chain-length prenyl pyrophosphate synthase. Plant physiology 155, 1079-1090. * Equal contribution