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MRC DiMeN Doctoral Training Partnership: Targeting cancer through disruption of the ubiquitin economy


Project Description

A PhD project in the shared laboratory of Prof. Michael Clague and Prof. Sylvie Urbé http://pcwww.liv.ac.uk/~clague/ in collaboration with an industry partner.

For proteins which drive tumour initiation and progression, it is desirable to suppress their levels by promoting their degradation by the proteasome, autophagy or trafficking to the lysosome. The ubiquitin system influences each pathway and plays a key role in determining the turnover rate of individual proteins. It presents a number of emerging therapeutic targets, drawn from >600 components. Our laboratory is focused on establishing the deubiquitylase (DUB) family of enzymes, as an exciting new class of drug targets.

In this project we will study a specific DUB family member, with a view to understanding its cellular functions. Identification of vulnerabilities imposed by loss of enzyme function is hoped to lead to a clinical positioning strategy for inhibitors of the enzyme in the area of cancer. A collaborating pharmaceutical company will provide tool compound inhibitors for characterisation and development. The student will gain experience of both fundamental cell biology and drug discovery science (including a 3 month secondment with the industrial partner). Almac Discovery: https://www.almacgroup.com/discovery/

All manner of techniques will be used that advance the programme. These are likely to include cell culture, live cell imaging, CRISPR/Cas9 gene editing, proteomics, RNAseq, bioinformatic analysis, enzyme assays etc.

Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme can be found on our website:
http://www.dimen.org.uk/

Funding Notes

iCASE Award: Industrial partnership project
Fully funded by the MRC for 3.5yrs, including a minimum of 3 months working within the industry partner. Enhanced stipend, tuition fees and budget for consumables, travel and subsistence.
Studentships commence: 1st October 2020.

To qualify, you must be a UK or EU citizen who has been resident in the UK/EU for 3 years prior to commencement. Applicants must have obtained, or be about to obtain, at least a 2.1 honours degree (or equivalent) in a relevant subject. All applications are scored blindly based on merit. Please read additional guidance here: View Website
Good luck!

References

Clague,M.J., Urbé,S. and Komander,D. Breaking the chains: deubiquitylase specificity begets function. (2019) Nature Reviews in Molecular Cell Biology, 20, 338-352.

Turnbull,A.P., et al. (2017) Molecular basis of USP7 inhibition by selective small molecule inhibitors, full article at Nature, 550, 481-486.

Clague,M.J., Heride, C., Urbé,S. (2015) The demographics of the ubiquitin system Trends in Cell Biology, 25, 417-426.

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