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  MRC DiMeN Doctoral Training Partnership: Understanding spatio-temporal GSK-3β activity in hematopoietic stem cells to improve regenerative medicine


   MRC DiMeN Doctoral Training Partnership

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  Dr Ines Hahn, Dr William Grey, Prof D G Kent  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

Haematopoietic stem cells (HSCs) are rare, highly potent cells that are responsible for life-long maintenance of our blood system. HSCT (transplantation) was the first regenerative medicine to enter the clinic and is a major component of gene therapy treatments. Unfortunately, issues remain, including our ability to expand these cells pre-transplantation and maintain cells in vitro for gene editing and therapy. Thus, a better understanding of HSC biology will unlock potential new therapeutic approaches for HSCT.

HSCs are highly quiescent but must respond rapidly to stress. Consequently, homeostasis of HSCs is a complex process that must be regulated by signalling. Glycogen Synthase Kinase-3β (GSK-3β) is a master regulator of HSCs, modulating stress responses and self-renewal. Importantly, GSK-3β activity levels regulate HSC expansion, making it a highly promising target. We propose the selective modulation of GSK-3β in time and space as an innovative novel strategy to tackle current obstacles in HSCT. You will take a crucial step towards this by visualising spatio-temporal GSK-3β dynamics in HSCs for the first time. To do this, you will develop targeted strategies to modify GSK-3β function to boost HSCs expansion and maintenance for gene therapy and transplantation. The project aims are to:

  1. Explore spatio-temporal GSK3b activity in healthy human and mouse HSCs during classical and novel expansion protocols.
  2. Determine timeline of changes in GSK-3β activity when HSCs engraft recipients and reform the blood system.

This project is highly interdisciplinary in nature and you will receive training in cutting-edge imaging approaches at York’s world-leading Technology facility, including FRET and live imaging, molecular genetics, gold-standard human healthy and cancer stem cell cultures, in vivo transplantation approaches and single cell protein biology. The project will be hosted in the York Biomedical Research Institute within the cutting-edge imaging facilities and thriving research environment of the York Biomedical Research Institute. It is a collaboration between Dr Ines Hahn, Dr William Grey and Prof David Kent and the Anthony Nolan Trust (the largest transplantation service in the U.K.), a supervisory team with extensive experience to provide tailored supervision.

You will work in a collaborative space between five research groups and benefit from attending the core haematology weekly meeting, weekly meetings with all supervisors and quarterly meetings with collaborative partners. Together with conference attendance and core training programme, this studentship will provide the upmost training in translational cell biology.

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: https://www.dimen.org.uk/blog 

Further information on the programme and how to apply can be found on our website: https://www.dimen.org.uk/how-to-apply 


Biological Sciences (4) Engineering (12) Medicine (26)

Funding Notes

Studentships are fully funded by the Medical Research Council (MRC) for 4yrs. Funding will cover tuition fees, stipend (£18,622 p.a. for 2023/24) and project costs. We also aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of full studentships to international applicants. Please read additional guidance here: https://www.dimen.org.uk/eligibility-criteria
Studentships commence: 1st October 2024
Good luck!

References

Grey et al., 2023, The CKS1/CKS2 Proteostasis Axis Is Crucial to Maintain Hematopoietic Stem Cell Function. Hemasphere; doi: 10.1097/HS9.0000000000000853
Grey et al., 2022, CKS1 inhibition reveals vulnerabilities in leukemic stem cells with concomitant protection of healthy hematopoietic stem cells. Science Translational Medicine; doi: 10.1126/scitranslmed.abn3248
Machado et al., 2023, Convergent somatic evolution commences in utero in a germline ribosomopathy. Nature Comms. https://doi.org/10.1038/s41467-023-40896-5
Che et al., 2022, Identification and characterization of in vitro expanded hematopoietic stem cells. EMBO Reports, https://doi.org/10.15252/embr.202255502

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