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MRC DiMeN Doctoral Training Partnership: Mechanisms of chronic liver disease associated with hepatitis C virus genotype 3 infection

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  • Full or part time
    Prof M Harris
    Dr F Oakley
    Prof D Mann
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Supervisors: Professor Mark Harris, Faculty of Biological Sciences, University of Leeds and Professor Fiona Oakley, Institute of Cellular Medicine, Newcastle University.

Background: Hepatitis C virus (HCV) infects 70 million individuals worldwide, leading to chronic liver disease. HCV is highly variable and is classified into 7 genotypes (GT), of which GT3 is the second most common, accounting for 30% of HCV cases worldwide, 50% in the UK and up to 70% in LMIC such as Pakistan, India and Thailand. GT3 is characterised by both a high level of resistance to the newly-developed direct-acting antiviral agents (DAAs), and also a more rapid progression to chronic liver disease compared to other GTs.
GT3 infection therefore remains of major concern and the objectives of this studentship are to understand the underlying mechanisms by which HCV GT3 leads to chronic liver disease. To achieve this aim the study will combine recent developments in culture systems for HCV GT3, with a novel bioreactor technology for modelling liver fibrosis in precision-cut liver slices (PCLS) that enables these cultures to be maintained for up to 6 days.

Experimental strategy and training:
The studentship will provide interdisciplinary training in a variety of state-of-the-art virological and cell biological techniques. Initially the student will establish robust replication and propagation of GT3 HCV in the Harris laboratory (Leeds), this will involve training to work safely at Biological Safety Level 3 (BSL3) with a human pathogenic virus. Part of this aspect of the project will include the use of clinical isolates obtained from the MRC Stratified Medicine Consortium ‘STOP-HCV’ and the Medical Research Foundation funded UK biobank ‘HCV Research UK’. In the Oakley laboratory (Newcastle) the student will be trained to produce and propagate PCLS, this technology will then be imported to Leeds. PCLS will be infected with HCV GT3 at BSL3 and a range of parameters studied. For example: effects of infection on fibrosis markers will be monitored, followed by both transcriptomic and proteomic analysis of infected PCLS. Analysis of cell morphology will be assessed using the state-of-the-art bioimaging facilities in Leeds, including super-resolution and correlative light-electron microscopy. These experiments will build a detailed picture of the effects of HCV GT3 infection on liver cell biology.

https://biologicalsciences.leeds.ac.uk/molecular-and-cellular-biology/staff/77/professor-mark-harris
https://www.ncl.ac.uk/icm/people/profile/fionaoakley.html#background

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 benefitted 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: https://goo.gl/8YfJf8
Good luck.

References

Paish H…& Oakley F. A novel bioreactor technology for modelling fibrosis in human and rodent precision-cut liver slices. bioRxiv preprint doi.org/10.1101/331173

Yin C, Goonawardane N, Stewart H and Harris M. A role for domain I of the hepatitis C virus NS5A protein in virus assembly PLOS Pathogens 2018 14(1):e1006834 doi:10.1371/journal.ppat.1006834

Kelly L, Badhan A, Roberts GC, Mbisa JL and Harris M. Manipulation of both virus- and cell-specific factors is required for robust transient replication of a hepatitis C virus genotype 3a sub-genomic replicon. J Gen Virol 2017 doi:10.1099/jgv.0.000932



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