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Precision Medicine DTP - Analysis of signaling pathways underlying development of human haematopoietic stem cells (HSCs)

  • Full or part time
    Prof A Medvinsky
    Dr K Kaji
    Dr A Ivens
  • Application Deadline
    Wednesday, January 08, 2020
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Background

Haematopoietic stem cells (HSCs) are broadly used in the clinic to treat blood disorders, but there is a shortage of these cells to meet clinical demands. Despite extensive efforts, the search for methods to produce high quality HSCs in the laboratory has had only limited success, mainly due to poor understanding of how these cells first emerge in the embryo. This project will address this gap by investigating molecular mechanisms leading to the generation of adult-type HSCs in the human embryo.

During development, HSCs emerge in the embryonic aorta-gonads-mesonephros (AGM) region and possess enormous regenerative potential, significantly exceeding that of HSCs from adult tissues. Determining the mechanisms underpinning this high regenerative potential could pave the way to generating bona fide HSCs in the laboratory from alternative cell sources such as pluripotent (ES/iPS) cells. While ES/iPS cells can produce blood cells, they fail to generate bona fide HSCs in culture. This raises important questions: which intrinsic genetic factors missing in ES cells are responsible for HSC formation in the human embryo and how do extrinsic niche (microenvironment) factors regulate HSC development? We will identify such genes and functionally characterize their action using combinatorial gene interrogation (reprogramming strategies) empowered by bioinformatics analysis. Using state-of-the-art single cell transcriptome analyses we will (1) identify which genes are working in HSCs of the human AGM region, but not in their less regenerative counterparts that are derived from human pluripotent (ES) cells and (2) introduce these genes into human pluripotent (ES) cells, to determine their effects on production of blood cells and thereby identify genes that may enhance production of transplantable HSCs. Resultant datasets will be used to (3) generate a computational model that integrates genetic regulators of HSCs and their microenvironment, which will be a highly valuable resource in the field.

Training outcomes

The student will learn: i. tissue culture methods and haematopoietic differentiation of human ES cells; ii. multi-colour flow cytometry and confocal microscopy; iii. reprogramming methodology using complex lentiviral libraries for combinatorial Dox-inducible overexpression of genes; iv. quantitative skills: analysis of single-cell transcriptomics datasets and computational modelling of cell-cell molecular interactions.

This MRC programme is joint between the Universities of Edinburgh and Glasgow. You will be registered at the host institution of the primary supervisor detailed in your project selection.

All applications should be made via the University of Edinburgh, irrespective of project location. For those applying to a University of Glasgow project, your application along with any supporting documents will be shared with University of Glasgow.

http://www.ed.ac.uk/studying/postgraduate/degrees/index.php?r=site/view&id=919

Please note, you must apply to one of the projects and you must contact the primary supervisor prior to making your application. Additional information on the application process is available from the link above.

For more information about Precision Medicine visit:
http://www.ed.ac.uk/usher/precision-medicine

Funding Notes

Start: September 2020

Qualifications criteria: Applicants applying for a MRC DTP in Precision Medicine studentship must have obtained, or will soon obtain, a first or upper-second class UK honours degree or equivalent non-UK qualification, in an appropriate science/technology area.
Residence criteria: The MRC DTP in Precision Medicine grant provides tuition fees and stipend of at least £15,009 (RCUK rate 2019/20) for UK and EU nationals that meet all required eligibility criteria.

Full eligibility details are available: View Website

Enquiries regarding programme:

References

1. Ivanovs, A., et al. (2017). "Human haematopoietic stem cell development: from the embryo to the dish." Development 144(13): 2323-2337

2. Ruetz, T., et al. (2017). "Constitutively Active SMAD2/3 Are Broad-Scope Potentiators of Transcription-Factor-Mediated Cellular Reprogramming." Cell Stem Cell 21(6): 791-805 e799

3. Wang, S., et al. (2019). "Cell lineage and communication network inference via optimization for single-cell transcriptomics." Nucleic Acids Res 47(11): e66.

Related Subjects

How good is research at University of Edinburgh in Biological Sciences?

FTE Category A staff submitted: 109.70

Research output data provided by the Research Excellence Framework (REF)

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