Leading science, pioneering therapies
Join us

PhD Opportunities

University funded PhD positions are advertised below. Please use the specific link on each project to apply.

Modelling foetal liver exposure to bisphenols and chemicals using an automated liver cell based platform

Applications closed (deadline Saturday 1st July, 5pm)

  • 1st Supervisor - Prof David Hay 
  • 2nd Supervisor - TBA

The project will be based at the MRC Centre for Regenerative Medicine and supervised by Dr David Hay. The cell type employed in these studies is the foetal liver progenitor cell which can been produced at scale from pluripotent stem cells (Lucendo-Villarin et al 2017, Archives of Toxicology). This was recently featured on the BBC website. The aim of the current project is to use our automated liver screening system to measure exposure to chemicals used in plastics, namely bisphenols, and compare exposure of those to a panel of compounds which are known to be toxic to the liver. The later will be provided by Astra Zeneca as part of an ongoing collaboration. Following the initial screens the successful candidate will focus on changes in foetal liver biology, with a view improving our understanding of foetal exposure and elucidating the molecular mechanisms that underpin this. The proposed studentship builds on existing expertise and active collaborations. The candidate will ideally have a background in cell biology and tissue culture. In addition to scientific merits, the successful candidate will be expected to be a team player and contribute to ongoing collaborations.

References

    1. Lucendo-Villarin B, Filis P , Swortwood MJ , Huestis MA, Meseguer Ripolles J , Cameron K , Iredale JP , O’Shaughnesy PJ , Fowler PA , Hay DC. Modelling foetal exposure to maternal smoking using hepatoblasts from pluripotent stem cells. Archives of Toxicology 2017. doi:10.1007/s00204-017-1983-0
    2. Scientists find that smoking harms livers of unborn babies - BBC website

    Further Information 

    This project is part of a funding competition. Due to fund source regulations, this studentship is only available to UK and EU nationals. For information on eligibility and stipend amounts, please click here.

    Novel therapeutic strategies to target cancer stem cells in acute myeloid leukaemia

    Applications closed (deadline Saturday 1st July, 5pm)

    • 1st Supervisor - Prof Kamil Kranc 
    • 2nd Supervisor - Prof Dónal O'Carroll

    Lifelong haematopoiesis critically depends on self-renewing haematopoietic stem cells (HSCs) that replenish progenitor cells and give rise to all blood lineages. Acute myeloid leukaemia (AML) is a clonal disorder of HSCs and progenitor cells, which acquire mutations and form treatment-resistant leukaemic stem cells that propagate the disease. Current therapies often fail to fully eradicate these cells, resulting in devastating disease relapses. As such, it is essential to identify new therapeutic targets to eliminate leukaemic stem cells. 

    Emerging evidence indicates that a group of enzymes referred to as 2-oxoglutarate-dependent oxygenases (2-OG-oxygenases) can hydroxylate fundamental proteins involved in gene transcription, RNA metabolism and protein synthesis to orchestrate multiple cellular processes. Interestingly, we have recently identified several 2-OG-oxygenases as critical regulators of leukaemic stem cell functions. We now intend to systematically investigate the functions of these 2-OG-oxygenases in leukaemic stem cell biology and reveal the therapeutic significance of inhibiting these enzymes in leukaemias. 

    Firstly, we will genetically delete these enzymes and investigate the impact of this manipulation on both the development and maintenance of leukaemic stem cells in mouse models of AML. Secondly, we will establish the therapeutic potential of pharmacological inhibition of these enzymes in immunocompromised mice xenografted with human AML samples. Finally, we will identify molecular mechanisms through which these 2-OG-oxygenases function in leukaemic stem cells. Given that very little is known about the roles of 2-OG-oxygenases in leukaemic stem cell behavior, this project offers an opportunity for novel insights and discovery. Importantly, this work will provide invaluable research into novel therapeutic strategies in AML, ultimately impacting on human health. 

    This translational project will be in collaboration with Professors Sir Peter Ratcliffe, Chris Pugh and Chris Schofield at The University of Oxford. Notably, due to the diverse nature of the project, the student will obtain multidisciplinary training in state-of-the-art approaches in the fields of stem cell and cancer biology (tissue culture, confocal microscopy and flow cytometry), advanced mouse genetics (CRISPR gene knockout approaches), mouse models of human leukaemia, and “omics” approaches to cancer biology (RNA-seq, CLIP-seq, proteomics, and basics of computational biology). 

    References

    1. Guitart et al, J. Exp. Med. 214, 719-735 (2017)
    2. Vukovic et al, J. Exp. Med. 212, 2223-2234 (2015)
    3. Mortensen et al, J. Exp. Med. 208, 455-467 (2011)
    4. Kranc et al, Cell Stem Cell 5, 659-665 (2009)

    Further Information 

    This project is part of a funding competition. Due to fund source regulations, this studentship is only available to UK and EU nationals. For information on eligibility and stipend amounts, please click here.

    Production of blood cells from pluripotent stem cells

    Applications closed (deadline Saturday 1st July, 5pm)

    • 1st Supervisor - Prof Lesley Forrester
    • 2nd Supervisor - TBA

    The production of functional blood cell types from human pluripotent stem cells (hPSCs) is a much sought after goal for modeling haematopoietic disease and cell therapy. However, many hPSC differentiation protocols are inefficient and unreliable and often it has not been possible to produce fully functional adult-like cells. For example, hPSC-derived haematopoietic progenitor cells (HPCs) are not capable of providing long-term haematopoietic support and red blood cells (RBCs) do not enucleate efficiently nor undergo appropriate globin switching. This has severely hampered the worldwide attempts to provide a consistent supply of infection-free, immunologically compatible cells to treat haematological disease. Many groups, including our own have shown that overexpression of specific transcription factors can enhance the production and differentiation of blood cells from hPSC (Jackson et al., 2016, Yang et al., 2016). Although this has been a successful approach it is challenging to translate this genetic engineering strategy into a clinic setting. We are also taking an alternative approach that involves tagging the expression of the key haematopoietic transcription factors with fluorescent reporters and manipulating culture conditions to enhance the production of cell types that express these programing factors. We have identified a list of transcription factors that are predicted to drive haematopoietic differentiation and have developed a strategy to generate reporter hPSC lines that track the expression of some of these genes. This project will involve the generation of new reporter hPSC lines and real-time imaging strategies to monitor the production of haematopoietic progenitor cells in vitro to identify the most efficient culturing protocols for blood cell production.  We have an active collaboration with an industrial partner, Plasticell who have developed a Combinatorial screening strategy that allows for the testing of large numbers of differentiation condition. 

    Techniques

    • Pluripotent stem cell culture and differentiation
    • Vector construction and genetic engineering of pluripotent stem cells
    • Flow cytometry
    • Imaging

    References

    1. Jackson, M., Ma, R., Taylor, A.H., Axton, R., Easterbrook, J., Olivier, E., Marenah, L., Stanley, E.G., Andrew G. Elefanty, A.G, Mountford, J.C. & Forrester, L.M. (2016). Enforced expression of HOXB4 in human embryonic stem cells enhances the production of haematopoietic progenitors but has no effect on the maturation of red blood cells. Stem Cells Translational Medicine 5:981-990.
    2. Yang, C-T., Ma, R., Axton, R., Jackson, M., Taylor, H., Fidanza, A., Marenah, L., Frayne, J., Mountford, J & Forrester, L.M. (2016). Activation of KLF1 Enhances the Differentiation and Maturation of Red Blood Cells from Human Pluripotent Stem Cells. Stem Cells 10.1002/stem.2562

    Further Information 

    This project is part of a funding competition. Due to fund source regulations, this studentship is only available to UK and EU nationals. For information on eligibility and stipend amounts, please click here.

    Dissecting heterogeneity in human pluripotent stem cell-derived dopaminergic neuronal grafts

    Applications closed (deadline Saturday 1st July, 5pm)

    • 1st Supervisor - Dr Tilo Kunath 
    • 2nd Supervisor - TBA

    Parkinson’s disease (PD) is an incurable neurodegenerative disorder that affects between 8-10 million people worldwide. Grafting of human fetal midbrain tissue into the striatum of PD patients has demonstrated that a transplantation therapy can restore dopamine transmission to normal levels and significantly reduce morbidity for at least 15 years. However, fetal tissue has considerable ethical and logistical challenges precluding its widespread therapeutic application. An alternate cell source is clinical-grade midbrain dopaminergic (mDA) cells differentiated from human pluripotent stem cells (hPSCs)1,2. We have established a new mDA cell production paradigm that is precise, robust, and cost-effective through development of tools and methodologies to scale up hPSC-based therapies for PD. However, the midbrain region is very complex with three major dopaminergic systems; A8 (retrorubral area), A9 (substantia nigra), and A10 (ventral tegmental area), with the A9 neurons most severely affected in PD. The A9 nigral neurons can also be subdivided into regions, such as dorsal and ventral tier of the SN, and it is unclear whether they have differing efficacy upon transplantation. Recent single-cell molecular profiling has described at least 6 distinct mDA subtypes in rodents3. In order to characterize and quantify the different mDA subtypes present in human ESC/iPSC differentiated cultures, we will take advantage of emerging single-cell transcriptomic technologies. We expect to find a similar level of complexity, if not more, in our human hPSC-derived mDA populations. Combinatorial expression of known (PITX3, NURR1, EN1) and novel mDA-specific transcription factors and cell surface proteins will be used to dissect the heterogeneity of cell types in hPSC differentiated cultures, and determine which combinations of cells are most effective at restoring dopaminergic function in rodent models of PD.

    Techniques

    • Human pluripotent stem cell culture
    • Differentiation of midbrain dopaminergic neurons
    • Immunofluorescence, confocal microscopy
    • Quantitative RT-PCR, RNA-seq, single cell RNA-seq
    • Fluorescence activated cell sorting (FACS)

    References

    1. Devine MJ, Ryten M, Vodicka P, Thomson AJ, Burdon T, Houlden H, Cavaleri F, Nagano M, Drummond NJ, Taanman JW, Schapira AH, Gwinn K, Hardy J, Lewis PA, Kunath T. (2011) Parkinson's disease induced pluripotent stem cells with triplication of the α-synuclein locus. Nat Commun. 2:440
    2. Canham MA, Van Deusen A, Brison DR, De Sousa PA, Downie J, Devito L, Hewitt ZA, Ilic D, Kimber SJ, Moore HD, Murray H, Kunath T. (2015) The Molecular Karyotype of 25 Clinical-Grade Human Embryonic Stem Cell Lines. Sci Rep. 5:17258
    3. Poulin JF, Zou J, Drouin-Ouellet J, Kim KY, Cicchetti F, Awatramani RB. (2014) Defining midbrain dopaminergic neuron diversity by single-cell gene expression profiling. Cell Rep. 9:930-43

    Further Information 

    This project is part of a funding competition. Due to fund source regulations, this studentship is only available to UK and EU nationals. For information on eligibility and stipend amounts, please click here.

    Growing a new type of progenitor cell with potential for repair of spinal cord or muscle

    Applications closed (deadline Saturday 1st July, 5pm)

    • 1st Supervisor - Prof Val Wilson 
    • 2nd Supervisor - TBA

    Neuromesodermal progenitors (NMPs) are a recently characterised type of progenitor cell, found in vertebrate embryos. They make the spinal cord, vertebrae and skeletal muscle (Wilson et al. 2009). In the embryo, they make first the head, then the neck, trunk and finally the tail, and are then eliminated from the embryo. They mature through a series of states characteristic of the differentiated cells they are about to produce. We can generate NMPs in vitro from mouse and human pluripotent cells (Tsakiridis et al. 2014, Gouti et al. 2014). It would be of significant clinical interest if we were able to control their maturation such that they could either proliferate indefinitely in one state, or give rise to cell types that are destroyed in diseases such as multiple sclerosis, or in spinal cord injury. However, conditions to keep them in any NMP state have so far been difficult to find. In unpublished work, we have investigated signalling pathways that control their maintenance and differentiation, as well as environmental conditions that prolong their maintenance. 

    In this project, the activity of candidate signalling pathways, extracellular matrix molecules and other physical constraints on the cellular environment will be systematically investigated with the aim of controlling the intrinsic timing mechanisms operating in NMPs, as well as their differentiation towards either neural or mesodermal (vertebrae/muscle) fates. Our standard model for testing functionality is to graft cells into appropriate sites in early embryos that then undergo ex vivo culture for up to 48 hours. Other models for testing more long-term functionality may also be explored, for example grafting into larval zebrafish, or into mouse embryos in utero.

    Techniques

    • Stem cell and primary tissue culture of organoids
    • Immunofluorescence and digital image analysis; confocal imaging
    • Quantitative RNA analysis 
    • Fluorescence activated cell sorting (FACS)

    Learning outcomes

    • Independent working and teamwork
    • Organisational skills and timekeeping
    • Critical thinking
    • Oral and poster presentation skills
    • Manuscript preparation

    References

    1. Wilson, V., Olivera-Martinez, I. and Storey, K. G. (2009). Stem cells, signals and vertebrate body axis extension. Development 136, 1591–1604. 
    2. Tsakiridis, A., Huang, Y., Blin, G., Skylaki, S., Wymeersch, F., Osorno, R., Economou, C., Karagianni, E., Zhao, S., Lowell, S., et al. (2014). Distinct Wnt-driven primitive streak-like populations reflect in vivo lineage precursors. Development 141, 1209–1221.
    3. Gouti, M., Tsakiridis, A., Wymeersch, F. J. and Huang, Y. (2014). PLOS Biology: In Vitro Generation of Neuromesodermal Progenitors Reveals Distinct Roles for Wnt Signalling in the Specification of Spinal Cord and Paraxial Mesoderm Identity. PLoS Biol. 12 e1001937

    Further Information 

    This project is part of a funding competition. Due to fund source regulations, this studentship is only available to UK and EU nationals. For information on eligibility and stipend amounts, please click here.




    Tissue Repair PhD Programme

    Applications will open again October 2017 for this programme

    University of Edinburgh/Wellcome Trust Tissue Repair Four Year PhD Programme

    The Centre for Regenerative Medicine is one of five key research centres involved in an innovative and exciting new Wellcome Trust Four-year PhD Programme in Tissue Repair, run by the University of Edinburgh and funded by the Wellcome Trust. The Tissue Repair PhD Programme provides cutting edge, cross-disciplinary PhD training which builds on the breath of world-class biomedical research performed at the University of Edinburgh's College of Medicine & Veterinary Medicine (CMVM).

    Tissue Repair Programme Website



    We encourage enquiries and applications from self-funded basic and clinical scientists and from candidates who intend to apply for external funding all year round.

    Instructions on how to apply as a self funded student can be found here.

    Please contact the relevant PI’s informally to discuss potential projects and visit our funding opportunities page.

    Centre Funded Studentships include:

    • Stipend for 3 or 4 years
    • Tuition Fees
    • Research Training Costs
    • Conference Travel Allowance

    Further information about MRC Studentships.

    Contact us for more information.