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MRC DiMeN Doctoral Training Partnership: Development of deubiquitylase (DUB) inhibitors to target interferon-mediated diseases


Project Description

We are excited to offer a PhD studentship to study deubiquitylating (DUB) enzyme inhibitors and their potential as therapeutics for interferon-mediated diseases.

Scleroderma (SSc) and Systemic Lupus Erythematosus (SLE) are interferon-mediated chronic autoimmune diseases with the highest morbidity and mortality among rheumatologic conditions. We aim to develop first-in-class DUB inhibitors that reduce inflammatory receptor signalling.

The studentship offers a unique opportunity to experience collaborative research between the ubiquitin signalling laboratory (Dr Elton Zeqiraj) and two clinical research groups who study interferon-mediated diseases (Dr Francesco del Galdo and Dr Ed Vital). The project involves characterisation of small molecule inhibitors in cellular models of disease, and how DUB inhibition affects immune responses. The studentship also offers the opportunity to learn and practice cryo-EM techniques to uncover inhibitor mechanism of action and thus contribute to an exciting early stage drug discovery program.

Ubiquitylation of proteins is a post-translational signal that regulates virtually all cellular processes through the precise spatial and temporal control of protein stability, activity or localization. As such, enzymes that perform ubiquitin chain cleavage (called deubiquitylases or DUBs), are frequently mutated in disease and important drug targets in cancer, autoimmune disease and neurodegeneration.

The project will be conducted at the University of Leeds in the Faculty of Biological Sciences and the Faculty of Medicine. The Zeqiraj laboratory is based at the Astbury centre, which offers a vibrant research environment and state-of-the art infrastructure for structural biology, drug discovery, chemical biology and proteomics. Drs. Del Galdo and Vital are based at the Leeds Institute of Rheumatic and Musculoskeletal Medicine, which is world-leading in research of rehabilitative and musculoskeletal medicine.

Techniques you will learn and use:
- Cryo-electron microscopy (Cryo-EM) for determining structures of proteins
- Cell biology and cellular imaging assays
- Gene expression arrays, qRT-PCR
- Fluorescence-activated cell sorting (FACS)
- Enzyme kinetic measurements and enzyme inhibition

For more information, please visit the following websites:

Dr Elton Zeqiraj laboratory:
http://www.personal.leeds.ac.uk/~fbsez/

Dr Francesco Del Galdo laboratory:
http://medhealth.leeds.ac.uk/profile/760/662/francesco_del_galdo

Dr. Ed Vital laboratory:
https://medhealth.leeds.ac.uk/profile/740/858/edward_vital/

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

Studentships are fully funded by the Medical Research Council (MRC) for 3.5yrs
Includes:
Stipend at national UKRI standard rate
Tuition fees
Research training and support grant (RTSG)
Travel allowance
Studentships commence: 1st October 2019.

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

Zeqiraj et al, (2015) Molecular Cell (https://www.ncbi.nlm.nih.gov/pubmed/26344097)

Liakouli et al, (2018) Ann Rheum Dis.
https://www.ncbi.nlm.nih.gov/pubmed/29259049

Zayat et al, (2018) Rheumatology
https://www.ncbi.nlm.nih.gov/pubmed/?term=30265343

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