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MRC DiMeN Doctoral Training Partnership: The development of physiologically and clinically relevant liver models for drug screening and development


MRC DiMeN Doctoral Training Partnership

Liverpool United Kingdom Biochemistry Bioinformatics Cell Biology Data Analysis Molecular Biology Pharmacology Physical Chemistry

About the Project

A major challenge in the development of novel efficacious drugs is drug-induced liver injury (DILI) which contributes to patient morbidities and mortalities. This ultimately puts an increased cost to the pharmaceutical industries and the health care system. Specifically, the failure of many medicines in clinical development is often associated with DILI - this is mainly due to the inability of pre-clinical safety testing models to predict clinical outcomes. Part of this problem is because DILI encompasses complex multi-factorial patient-specific processes that are difficult to recapitulate with simple in vitro systems. Therefore, there is a need for more representative pre-clinical in vitro models to successfully predict clinical outcomes.

This multidisciplinary PhD project will provide a broad training in key areas for drug development of the future - primary human cell culture, 3D in vitro models, proteomics and next generation sequencing as well as exposure to business development training within an industrial setting. The student will study in an academic-industrial partnership, with an overall aim to develop clinically and physiologically relevant tissue-mimicking models to improve drug discovery and development. The PhD will be based at the MRC Centre for Drug Safety Science (CDSS) (https://www.liverpool.ac.uk/mrc-centre-for-drug-safety-science/), and (Twitter: @CDSS_Liverpool) working with primary supervisor Prof. Chris Goldring (University of Liverpool), second supervisor Prof. Aline Miller (University of Manchester; Twitter: @alinefmiller) and third supervisor Dr. Adedamola (Dammy) Olayanju (Manchester BIOGEL; twitter @Mancbiogel). This collaborative project will involve the combined expertise of drug safety scientists and material scientists at the two research-led universities (UoL and UoM), an industrial partner (Manchester BIOGEL) and surgeons at a local teaching hospital to develop and validate a patient-specific 3D cell culture platform capable of maintaining cells in their natural 3D configuration. 

More specifically, the project will develop and optimise in vitro models that fully mimic the native liver by combining tuneable self-assembling peptide hydrogel scaffolds with donated liver tissues (we have an unfettered access to human liver tissues through a longstanding collaboration with the hepatobiliary surgical unit at a local teaching hospital). The successful student will have access to material science design and characterisation expertise, as well as business development, training at Manchester BIOGEL to develop fully representative tissue-specific scaffolds with commercial potential.

The developed tissue-mimicking models will be analysed with robust proteomics tools combined with the use of next generation sequencing (NGS) of the major liver cell types. Findings from this analysis will inform us about how physiologically and clinically representative our model is. It will also inform us about inter-individual variation in the expression of liver-specific markers. In addition, it will also give an indication as to how patient-specific cells respond to DILI. The final part of the project will involve the (i) dose- and time-dependent toxicity of a small panel of DILI-specific drugs (ii) collaboration with Pharmaceutical industry partners (the primary supervisor has established funded links with many UK, EU and US pharma companies) to (a) carry out multi-site validation of the reproducibility of our approach and to (b) potentially validate the findings with Pharma legacy compounds.

Overall, this project represents an excellent opportunity for multidisciplinary PhD training in many key research skills that will be highly relevant to future drug development as well as improving models of human tissue function.

iCASE Partner

This project is part of the Discovery Medicine North Doctoral Training Partnership, 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

Further information on the programme and how to apply can be found here


Funding Notes

Funded by the MRC for 3.5yrs, including a minimum of 3 months working within the industry partner.

Funding will cover UK tuition fees and an enhanced stipend (around £17,785) only. We aim to support the most outstanding applicants from outside the UK. We 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

• Weaver et al. Managing the challenge of drug-induced liver injury: a roadmap for
the development and deployment of preclinical predictive models. Nat Rev Drug Discov. 2020;19: 131-148. doi: 10.1038/s41573-019-0048-x.
• Heslop JA, et al. Donor-Dependent and Other Nondefined Factors Have Greater Influence on the Hepatic Phenotype Than the Starting Cell Type in Induced Pluripotent Stem Cell Derived Hepatocyte-Like Cells. Stem Cells Transl Med. 2017;6:1321-1331. doi: 10.1002/sctm.16-0029.
• A. Faroni, et al. Self-assembling peptide hydrogel matrices improve the neurotrophic potential of human adipose-derived stem cells. Advanced Healthcare Materials. 2019;8;1900410 doi: 10.1002/adhm.201900410.

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