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China Scholarship Council - Exploiting Affinity-directed Protein Missile system to target destruction of misfolded proteins in neurodegeneration

  • Full or part time
    Dr Gopal Sapkota
  • Application Deadline
    Wednesday, January 15, 2020
  • Competition Funded PhD Project (Students Worldwide)
    Competition Funded PhD Project (Students Worldwide)

Project Description

The School of Life Sciences at the University of Dundee, joint with the China Scholarship Council (CSC), is proud to be able to offer a scholarship programme for postgraduate research students. The scholarship covers all tuition fees and research fees and provides living expenses and one return flight ticket to successful candidates. There are up to 5 scholarships of 4 years duration available.

Project Description

Ubiquitin proteasome system (UPS) controls protein turnover in cells in order to maintain cellular homeostasis (1). E3 ubiquitin ligases facilitate the process of attaching ubiquitin on sustrate proteins. By recruiting E3 ubiqutin ligases to the Proteins of Interest (POIs), we can target specific POIs for UPS-mediated degradation, for example by small molecule proteasome targeting chimeras (PROTACs). We have developed a proteolytic Affinity-directed PROtein Missile (AdPROM) system by utilising small polypeptide binders of POIs and distinct E3 ubiquitin ligases or substrate receptors of E3 ligases for rapid and efficient degradation of POIs (2,3). The AdPROM system is not only useful for targeted degradation of any intracellular protein to study its function, but rapidly informs the druggability of POIs so that small molecule degraders can be designed. This project will employ the AdPROM system to interrogate: i. what families of E3 ubiquitin ligases are capable of POI ubiquitination for targeted proteolysis? Answering this will allow choice of E3 ubiquitin ligases that may be selective to specfici tissue context based on expression levels and activity and will potentially allow selective proteolytic targeting; ii. what is the extent of target POI degradation in the context of subcellular distribution? Answering this will rapidly inform whether targeted degradation of a POI is the correct drugging approach; and iii. can we combine findings from above to engineer new small molecule recruiters of new E3 ligases for possible application in PROTACs?

Funding Notes

In order to be eligible for these awards applicants must:

Be a Chinese national
Meet the requirements of the CSC – please see their website
Hold an unconditional offer to study for a PhD at the University of Dundee and meet our English language requirements
Have completed bachelors or masters degree before the agreed start of PhD study.

References

1. Röth S, Fulcher LJ, Sapkota GP (2019) Advances in targeted degradation of endogenous proteins. Cell Mol Life Sci. 2019 Jul;76(14):2761-2777. doi: 10.1007/s00018-019-03112-6.
2. Fulcher, L. J., Macartney, T. J., Turnbull, C., Hutchinson, L., and Sapkota, G. P. (2017) Targeting endogenous proteins for degradation through the affinity-directed protein missile system. Open biology, 7: 170066. (8 citations)
3. Fulcher, L. J., Macartney, T., Bozatzi, P., Hornberger, A., Rojas-Fernandez, A. and Sapkota, G. P. (2016). An affinity-directed protein missile system for targeted proteolysis. Open Biol 6 DOI: 10.1098/rsob.160255. (12 citations)

How good is research at University of Dundee in Biological Sciences?

FTE Category A staff submitted: 73.20

Research output data provided by the Research Excellence Framework (REF)

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