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PhD opportunities

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

Optimising the production of blood cells from pluripotent stem cells using Combicult Technology (iCase)

Deadline for applications - Monday 16th April, 5pm

1st Supervisor: Prof Lesley Forrester
Industrial Partner: Dr Yen Choo

Background

The production of functional blood cell types from human pluripotent stem cells (hPSCs) for diseases modeling and cell therapy is a much sought after goal. However, many 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. An alternative approach is to tag the expression of the key transcription factors with fluorescent reporters and to then manipulation the culture conditions to enhance the production of cell types that express the key haematopoietic programing factors. We are in the process of generating single cell RNA sequencing datasets from differentiating hPSCs to identify important transcription factors at the early stages of the differentiation process. We have developed a CRISPR/CAS9 strategy to insert fluorescent tags into the hPSCS genome that allows us to track the expression of these key regulators. The aim of this project will be to generate and characterise new reporter PSC lines and to use them to develop improved culture protocols that reduce the time and cost and optimize the production of fully functional cell types. In collaboration with Plasticell we will use an innovate technology known as Combicult (http://www.plasticell.co.uk/technology/t) that allows the screening of many thousands of different culture conditions simultaneously (Tarunina et al., 2016).

Aims

The overall aim of the project will be to optimse the production of haematopoietic progenitor cells from human PSCs. 

  • Identify transcription factor regulators of haematopoietic differentiation. 
  • Generate and characterize iPSCs carrying fluorescent tags in key transcription factors 
  • Use Combicult and Ariadne Bioinformatics analysis to identify optimal culture conditions.

Training Outcomes

  • Genome editing: Use of CRISPR/CAS9 technology to generate human pluripotent stem cell reporter cell lines.
  • Cell culture: Maintenance and differentiation of human pluripotent stem cells
  • Industrial partnership: Combicult technology
  • Bioinformaticsand data analyses: Ariadne Bioinformatics analyses of Combicult data

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.
  3. Tarunina M, Hernandez D, Kronsteiner-Dobramysl B, Pratt P, Watson T, Hua P, Gullo F, van der Garde M, Zhang Y, Hook L, Choo Y, Watt SM (2016). A novel High-throughput platform reveals an optimized cytokine formulation for human hematopoietic progenitror cell expansion. Stem Cells Development (2016) 15;25(22):1709-1720.

Apply Now

Click here to apply now

  • The deadline for 18/19 applications is 5pm on Monday 16th April 2018.
  • Please note all applications for the Precision Medicine DTP should be submitted to University of Edinburgh, even those applying for a project at the University of Glasgow.
  • Applicants must apply to a specific project, ensure you include details of the project you are applying to in Section 4 of your application. We encourage you to contact the primary supervisor prior to making your application.  
  • As you are applying to a specific project, you are not required to submit a Research Proposal as part of your application. 
  • Please ensure you upload as many of the requested documents as possible at the time of submitting your application.  

Modelling foetal liver development and disruption using pluripotent stem cells (iCase)

Deadline for applications - Monday 16th April 2018, 5pm

1st Supervisor: Prof David Hay & Dr Carsten Hansen
Industrial Partner: Stemnovate Ltd.

Background

The project will be based at the MRC Centre for Regenerative Medicine and supervised by Prof David Hay. The cell type employed in these studies is the foetal liver progenitor cell which can been produced at scale in our lab from pluripotent stem cells (Lucendo-Villarin et al 2017, Archives of Toxicology, BBC News - http://www.bbc.co.uk/news/uk-scotland-40084844). The aim of the current project is to use our automated liver screening system to model foetal exposure to endocrine disruptors used in the manufacture of plastics, namely bisphenols. Following on from these experiments we will compare bisphenol exposure 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 and comparisons, the successful candidate will focus on the mechanistic changes that take place in foetal liver cell biology following bisphenol exposure using a range of established techniques. The proposed studentship builds on existing expertise and active academic and industrial 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.

Aims

Concern over the use of plastics in everyday life has been growing, because plastic contains hazardous chemicals and is poorly biodegradable. Considerable concern have been raised that plastic can disrupt the endocrine system in the humans. Endocrine disruptors such as bisphenol A (>3.5 billion kg produced annually) are known to program the developing foetuses for disease post-natally. The focus of the PhD project proposed is to better understand the threat that bisphenols pose to human health in utero. In particular we will study the developing liver, using stem cell derived hepatocyte models ‘in a dish ‘. Those models have already led to greater understanding on the effects of maternal smoking on liver development, providing proof of concept of our testbed (Villarin et al 2017 Arch Tox). In the proposed project we wish to further our understanding of the changes in cell signaling circuitry following exposure to bisphenols. We believe that such fundamental advances have the potential to improve human health during the lifetime of the individual. The output from these studies will provide mechanistic insight into the underlying cell biology, with a focus on improving foetal health, thereby reducing the need for medical and social interventions post-birth.

Training Outcomes

PhD students will be provided access to ‘state of the art’ facilities and technologies to build upon during their PhD project. During the PhD project, the student will be expected to attend UofE seminar series and to present the outcomes of their studies at local and international meetings. This is key to student development, identifying new networking opportunities, building capacity within the field and delivering high level impact. Additionally, the student will have the opportunity to work within industry on a three month placement at Stemnovate Ltd. This company delivers innovative drug-screening and safety-testing platforms. They employ flexible microfluidic platforms that overcome the limitations of current mammalian cell-lines and in-vivo models. The company is developing products in numerous areas of human liver biology.

Apply Now

Click here to apply now

  • The deadline for 18/19 applications is 5pm on Monday 16th April 2018.
  • Please note all applications for the Precision Medicine DTP should be submitted to University of Edinburgh, even those applying for a project at the University of Glasgow.
  • Applicants must apply to a specific project, ensure you include details of the project you are applying to in Section 4 of your application. We encourage you to contact the primary supervisor prior to making your application.  
  • As you are applying to a specific project, you are not required to submit a Research Proposal as part of your application. 
  • Please ensure you upload as many of the requested documents as possible at the time of submitting your application.  

Understanding haematopoietic stem cell development through global single-cell gene expression analysis

Deadline for applications - Monday 16th April, 5pm 

1st Supervisor: Prof Alexander Medvinsky 
2nd Supervisor: Dr Tamir Chandra

Background

The first blood cells in mammals appear in the yolk sac, however haematopoietic stem cells (HSCs) which give rise to the adult haematopoietic system appear inside the embryo body within the aorta-gonad-mesonephros (AGM) region (Medvinsky and Dzierzak, Cell, 1996). HSCs gradually mature in the AGM region before colonizing the foetal liver and subsequently bone marrow. However, genetic mechanisms underlying HSC development in mammals are poorly understood partly due to in utero development. We therefore established a culture system which replicates HSC development in the AGM region (Taoudi et al., Cell Stem Cell, 2008; Rybtsov et al., Stem Cell Reports, 2014). Using this system, we characterized the hierarchy of HSC precursors by cell surface markers. However, these markers are shared with other blood progenitors, which hampers precise identification of developing HSCs and genes which drive HSC development. 

Recent advancement in single-cell transcriptome analysis have transformed our understanding of cell types and lineages. It permits exploration of heterogeneity of cell populations and identification of novel cell sub-types which otherwise remain unrecognized. Using highly parallel barcoding of individual cells and computational tools specifically developed for single-cell data, it is now possible to build detailed developmental/ differentiation trees and identify key candidate genes underpinning HSC development (Macosko et al., Cell, 2015; Mohammed et al., Cell Reports, 2017). 

Aims

In this interdisciplinary project, we aim to explore molecular mechanisms underlying embryonic HSC development. The student will explore the transcriptional heterogeneity of the developing haematopoietic system in mouse embryo using system-wide single-cell transcriptome analysis. In addition to wild type, we will study gene expression changes in a key mouse mutant line where HSC development is blocked. This will allow us to dissect the entire gene network supporting HSC development. Single-cell gene expression analysis will be performed using cell barcoding in a microfluidics device. Using bioinformatics methods the student will reconstruct the developmental tree of the developing haematopoietic system and will identify molecular signatures specific to clades of the developing HSC lineage. Candidate genes identified in the molecular signature that could potentially be involved in HSC development will be validated using functional in vitro and in vivo approaches and their expression in the embryo will be characterized using confocal microscopy. Our data-driven approach using cutting-edge single cell methodology in mouse is expected to be highly informative for identifying homologous cellular differentiation pathways in human and will have substantial predictive power for analysing mechanisms underlying human HSC development. This project will fill a crucial gap in our mechanistic understanding of HSC development, which could in future inform improved strategies for manipulating HSCs ex vivo.

Training Outcomes

This is a collaborative interdisciplinary project addressing important biological questions at the system-wide level, between the groups of Prof. A. Medvinsky, an expert in embryonic development of mouse and human HSCs and groups of Dr. Chandra, experts in single cell analysis including computational analysis of single-cell data. To enhance the outcome of the project we have established a collaboration with Prof. Bertie Gottgens in Cambridge, a leading expert in the analysis of blood transcriptional networks. 

The student will work in a highly collaborative environment and will become proficient in advanced methods of early analysis of embryonic HSC development (embryo manipulations, fluorescence activated cell sorting and analysis, HSC culture, qRT-PCR, confocal microscopy) as well as single-cell analysis and computational biology methods. Importantly, UoE has been awarded a £650K MRC Discovery Award to implement Drop-Seq-like approaches to single cell transcriptomics. This creates an excellent opportunity for the student to become an expert in this rapidly evolving cutting-edge technology. The project will allow the student to obtain important insights into the analysis of complex biological systems and to acquire important interdisciplinary skills in systems biology approaches, which should have a highly positive impact on their future career in science. 

Apply Now

Click here to apply now

  • The deadline for 18/19 applications is 5pm on Monday 16th April 2018.
  • Please note all applications for the Precision Medicine DTP should be submitted to University of Edinburgh, even those applying for a project at the University of Glasgow.
  • Applicants must apply to a specific project, ensure you include details of the project you are applying to in Section 4 of your application. We encourage you to contact the primary supervisor prior to making your application.  
  • As you are applying to a specific project, you are not required to submit a Research Proposal as part of your application. 
  • Please ensure you upload as many of the requested documents as possible at the time of submitting your application. 

Tissue Repair PhD Programme

Applications are now closed for this programme 

Funded studentships available for Wellcome Trust PhD Programme inTissue Repair.

The MRC Centre for Regenerative Medicine is one of five research centres at the Edinburgh Medical School involved in the four-year PhD Programme in Tissue Repair. This innovative, multi-disciplinary training programme seeks to train the next generation of scientific leaders in tissue repair by providing interdisciplinary training in basic and translational biomedical research. The programme is run by the University of Edinburgh and funded by the Wellcome Trust. For programme details please visit the Tissue Repair website.

Tissue Repair 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.