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MRC DiMeN Doctoral Training Partnership: UCHL1 inhibition – a strategy to target aberrant HIF signalling in fibrotic liver disease?


MRC DiMeN Doctoral Training Partnership

Liverpool United Kingdom Biochemistry Biotechnology Cell Biology Genetics Human Genetics Molecular Biology Molecular Genetics

About the Project

Background

Liver disease is the third leading cause of premature death in the UK, accounting for over 40 deaths per day. Mortality rates for liver disease have increased 400% since 1970, and in those under the age of 65 years have risen almost five-fold, increasing the need for therapeutic interventions (British Liver Trust). There are currently no effective treatments to prevent liver fibrosis, the key driver of chronic liver disease, which at its advanced stage, can lead to cirrhosis, loss of liver function and death. Liver fibrosis occurs when injury or inflammation causes excessive amounts of scar tissue to build up in the organ. Work from our laboratories has demonstrated that hypoxia inducible factor 1 (HIF1), a transcription factor more commonly associated with the cellular response to low oxygen, is elevated in fibrotic liver cells. HIF activation promotes liver fibrosis by driving the expression of genes associated with vascular remodelling, futile angiogenesis and ECM deposition. 

Directly inhibiting HIF1 as a strategy to treat fibrosis is challenging due to its relatively disordered structure and the necessity to interfere with large protein–protein or protein–DNA interfaces. However, collaborative work from the supervisory team reveals that genetic and chemical inhibition of the deubiquitinating enzyme Ubiquitin C-terminal hydrolase-L1 (UCHL1) can reduce HIF1 levels in fibrotic liver cells. In addition, as UCHL1 levels are markedly elevated in fibrotic liver cells compared to surrounding healthy tissue, UCHL1 inhibition represents a targeted therapy for liver fibrosis.

Project Description and Experimental Approach

Using state of the art genome editing techniques (CRISPR/Cas9), and clinically relevant liver disease models, you will examine the relationship between UCHL1 and HIF signalling in the liver to investigate if UCHL1 inhibition has potential as a targeted therapeutic strategy treatment for liver fibrosis. Using pharmacological inhibitors of UCHL1, or UCHL1 genetic deletion, you will examine the phenotype of liver cells responding to pro-fibrogenic stimuli or hypoxic stress. In addition, you will examine the potential of using UCHL1 inhibitors to target HIF signalling in human precision-cut liver slices induced to undergo fibrosis by a variety of stimuli including lipids associated with liver disease. Together these experiments will define the relationship between UCHL1 and HIF during liver fibrosis and establish whether UCHL1 inhibition can down regulate HIF signalling as an anti-fibrotic therapy in chronic liver disease.

Training and Environment

The studentship will be based in Liverpool and benefit from being part of the large hypoxia-dependent signalling community in within the Institute. The placement in the Fibrosis Research Group in Newcastle University will provide training in clinically relevant models of liver disease. The depth of expertise at both institutions and the world class facilities available, will provide an excellent training environment for the student to develop and grow during their studies.

For informal enquiries contact Dr Niall Kenneth ()

Links

Dr Niall Kenneth

https://www.liverpool.ac.uk/integrative-biology/staff/niall-kenneth/

https://www.liverpool.ac.uk/integrative-biology/

Professor Derek Mann

https://www.ncl.ac.uk/medical-sciences/people/profile/derekmann.html

https://research.ncl.ac.uk/fibrosislab/

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 and how to apply can be found on our website:

https://bit.ly/3lQXR8A


Funding Notes

Studentships are funded by the Medical Research Council (MRC) for 3.5yrs. Funding will cover UK tuition fees and stipend only. We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme. Please read additional guidance here: View Website
Studentships commence: 1st October 2021
Good luck!

References

1 Park, C. V., Ivanova, I. G. and Kenneth, N. S. (2017) XIAP upregulates expression of HIF target genes by targeting HIF1α for Lys63-linked polyubiquitination. Nucleic Acids Res.
2 Wilson, C. L., Murphy, L. B., Leslie, J., Kendrick, S., French, J., Fox, C. R., Sheerin, N. S., Fisher, A., Robinson, J. H., Tiniakos, D. G., et al. (2015) Ubiquitin C-terminal hydrolase 1: A novel functional marker for liver myofibroblasts and a therapeutic target in chronic liver disease. J. Hepatol.
3 Ivanova, I. G., Park, C. V, Yemm, A. I. and Kenneth, N. S. (2018) PERK/eIF2α signaling inhibits HIF-induced gene expression during the unfolded protein response via YB1-dependent regulation of HIF1α translation. Nucleic Acids Res. 46, 3878–3890.

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