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Precision Medicine DTP - Analysis of signalling pathways that underlie the development of human haematopoietic stem cells


School of Biological Sciences

Prof A Medvinsky , Prof K Kaji , Dr A Ivens Thursday, January 07, 2021 Competition Funded PhD Project (Students Worldwide)

About the Project

Haematopoietic stem cells (HSCs) give rise to the adult blood system and are broadly used in clinical transplantations, however the demand for HSC transplants exceeds the current supply. Pluripotent (ES/iPS) cells can produce blood cells in vitro but fail to recapitulate the in vivo development of transplantable HSCs (Ivanovs et al., Development, 2017). We previously showed that during embryonic development, the first HSCs emerge in the AGM region (Medvinsky and Dzierzak, Cell, 1996) and possess vast self-renewing and regenerative potentials (Ivanovs et al., Stem Cell Reports, 2020). We have also mapped the molecular machinery that is associated with the early development of human HSCs (Crosse et al., Cell Stem Cell, 2020).

In this project, we will identify the key regulatory genes that govern the specification and self-renewal properties of the first emerging human HSCs, using conditional genetic manipulations of human ES cells followed by functional in vitro and in vivo studies. We will also investigate gene regulatory networks (GRN) that underlie early HSC development using bioinformatics tools, which will allow us to build integrative computational model depicting HSC- AGM niche molecular interactions. You will gain both practical laboratory experience in ES cell manipulations using reprogramming technologies, haematopoietic differentiation, molecular biology analyses (including single cell transcriptomics) and experience in computational (bioinformatics) analysis. This study will allow for better control of ex vivo HSC manipulations and will help move cell-based therapies towards a more personalized medicine approach.

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 2021

Qualifications criteria: Applicants applying for an 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. The MRC DTP in Precision Medicine grant provides tuition fees and stipend of at least £15,285 (UKRI rate 2020/21).

Full eligibility details are available: View Website

Enquiries regarding programme:

References

(1) Crosse, E. et al., (2020) . “Multi-layered spatial transcriptomics identify secretory factors promoting hematopoietic stem cell emergence in human development”. Cell Stem Cell, in press.
(2) Ivanovs et al. (2011). “Highly potent human hematopoietic stem cells first emerge in the intra-embryonic aorta-gonad-mesonephros region”. J. Exp. Med. 208:2417-2427
(3) Ivanovs, A., et al. (2017). "Human haematopoietic stem cell development: from the embryo to the dish". Development 144(13): 2323-2337.
(4) Ivanovs et al. “Vast self-renewal potential of human AGM region HSCs dramatically declines in the umbilical cord blood” (2020). Stem Cell Reports, in press.
(5) 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.
(6) Wang, S., et al. (2019). "Cell lineage and communication network inference via optimization for single-cell transcriptomics." Nucleic Acids Res 47(11): e66.

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