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MRC DiMeN Doctoral Training Partnership: Development of an osteoarthritis drug screening platform using engineered stem cell lines to identify novel mechanisms of disease biology

About the Project

Osteoarthritis (OA) is a painful and disabling disease of articulating joints with substantial healthcare and socioeconomic burden. The global incidence of OA, currently estimated at 250 million affected individuals, is predicted to rise with increased life expectancy and obesity rates, to become a leading cause of disability worldwide. Management of OA is primarily limited to pain relief; there are no approved disease-modifying OA drugs (DMOADs), hampered by the heterogeneous nature of OA and lack of appropriate pre-clinical test systems. We have developed an immortalised human clonal mesenchymal stem cell (MSC) line capable of differentiating into bone-forming osteoblasts and cartilage-forming chondrocytes, the primary joint tissues affected in OA. From this MSC line we engineered fluorescent and secreted luciferase reporters of osteogenic and chondrogenic status and inflammatory responses.

In this PhD project, working alongside industrial collaborators GSK, we will determine the feasibility of developing the MSC-based reporter system as a screening platform to identify DMOADs. We will undertake a comprehensive validation of our existing reporter lines to determine suitability for in vivo translation and scaled screening. We will engineer a dual reporter for simultaneous readouts of health and disease. Screening using this dual reporter has the potential to identify pathways that determine the balance of tissue formation versus degradation, which drives OA pathogenesis. We will identify a selection of regulators of osteogenesis and chondrogenesis using a small well-annotated set of chemical modifiers in conjunction with CRISPR/Cas9 gene editing and/or RNA silencing. This will enable us to demonstrate proof-of-concept and provide mechanistic insight into the regulation of MSC differentiation. Compounds identified by these screens will be taken forward for in-depth analysis of effects in osteogenic and chondrogenic differentiation assays. Later work will focus on scale-up, throughput and commercialisation. The proposed work has the potential to identify novel mechanisms responsible for joint tissue health and provide a highly valuable resource of OA drug discovery.

GSK and the University of York are passionate about recruiting the best talent irrespective of background. We strongly encourage applications from all backgrounds (social, cultural and educational). We are proud of championing the virtues of Equality, Diversity and Inclusion. We believe that no capable candidate should ever receive more favourable treatment, than any other, on the grounds of sex or gender assignment, physical or mental disability, marital status, HIV status, sexual orientation, pregnancy status, race, colour, nationality, ethnic or national origin, religion or belief. All assessments are made on merit alone. We have support to protect the health and well-being of all our staff and students, and we will make every effort to accommodate your personal circumstances, by adopting a flexible working/study pattern, to enable you to progress in your career whilst at the same time managing your personal circumstances. If you have the motivation to succeed, we will work with you, irrespective of your background or personal circumstances.

https://www.geneverlab.info/

https://twitter.com/genever_lab

https://medicinehealth.leeds.ac.uk/medicine/staff/2164/elena-jones

 

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, York 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:

http://www.dimen.org.uk/how-to-apply/application-overview

Funding Notes

iCASE Award: Industrial partnership project
Funded by the MRC for 4yrs, including a minimum of 3 months working within the industry partner.

Funding will cover UK tuition fees and an enhanced stipend (around £18,109). We also 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 be awarded to exceptional candidates only, due to the competitive nature of this scheme. Please read additional guidance here: View Website
Studentships commence: 1st October 2022
Good luck!

References

1. Wilson A, Hodgson-Garms M, Frith JE, Genever P. Multiplicity of Mesenchymal Stromal Cells: Finding the Right Route to Therapy. Front Immunol. 2019 May 16;10:1112. www.frontiersin.org/articles/10.3389/fimmu.2019.01112/full
2. James S, Fox J, Afsari F, Lee J, Clough S, Knight C, Ashmore J, Ashton P, Preham O, Hoogduijn M, Ponzoni Rde A, Hancock Y, Coles M, Genever P. Multiparameter Analysis of Human Bone Marrow Stromal Cells Identifies Distinct Immunomodulatory and Differentiation-Competent Subtypes. Stem Cell Reports. 2015 Jun 9;4(6):1004. https://doi.org/10.1016/j.stemcr.2015.05.005
3. McGonagle, D., Baboolal, T.G. and Jones, E. Native joint-resident mesenchymal stem cells for cartilage repair in osteoarthritis. Nature Reviews Rheumatology, 2017 13(12), pp.719-730. https://www.nature.com/articles/nrrheum.2017.182
4. Ilas, D.C., Baboolal, T.G., Churchman, S.M., Jones, W.G., Giannoudis, P.V., Bühring, H.J., McGonagle, D. and Jones, E. The osteogenic commitment of CD271+ CD56+ bone marrow stromal cells (BMSCs) in osteoarthritic femoral head bone. Scientific Reports, 2020 10(1), pp.1-14. https://www.nature.com/articles/s41598-020-67998-0