PhD opportunities

EASTBIO (College of Medicine and Veterinary Medicine) 

Identification of novel metabolic pathways regulating haematopoietic stem cell self-renewal

Applications accepted up to Friday 17th Janaury 2025

1st Supervisor: Dr. Stefano Comazzetto (University of Edinburgh) 

About the Project

A rare population of haematopoietic stem cells (HSCs) sustains life-long blood production. Highly sensitive metabolomic methods have recently discovered a few metabolic pathways controlling HSC maintenance and self-renewal. Notwithstanding these advances, the low numbers of HSCs isolated from tissues precluded the measurement of a significant fraction of the cell metabolome. We thus hypothesize that several other metabolic pathways control HSC self-renewal and function. To assess this previously inaccessible HSC metabolome, we propose to integrate metabolomic and proteomic data from millions of HSCs expanded in culture. To achieve this, my laboratory has established a novel culture system that allows to expand HSCs with physiological levels of metabolites found in their native microenvironment.

In this interdisciplinary project, the student will:1.    Characterize the metabolome and proteome of HSCs and progenitors expanded in culture, with expert guidance from Prof. Alex Von Kriegsheim (University of Edinburgh);2.    Analyse and combine the information from the generated datasets to identify novel metabolic pathways that potentially regulate HSC self-renewal, with expert guidance from Dr. Antonella Fidanza (University of Edinburgh);3.    Test the functional role of identified metabolic pathways on HSC self-renewal using available chemical inhibitors, with expert guidance from Prof. Katrin Ottersbach (University of Edinburgh) and Prof. Vignir Helgason (University of Glasgow).

The student will be part of a highly motivated and vibrant team working on how metabolites regulate normal and malignant haematopoiesis. This highly collaborative project will be primarily carried out at the Centre of Regenerative Medicine at the University of Edinburgh. To deliver this project, the student will receive training in cutting-edge wet lab techniques (HSC culture, flow cytometry analysis and sorting, sample preparation for metabolomics/proteomics, etc.), computational biology analysis (differential expression, enrichment and network analysis, etc.), written and oral communication of scientific findings through regular written reports, presentations at lab and institute level, and attendance to conferences/meetings. The student will gain significant experience in a range of disciplines (stem cell biology, metabolism, computational analysis), data and project management, and working collaboratively.

Understanding how metabolism regulate the self-renewal and function of stem cells is a fundamental question in biology. Our fundamental findings will potentially open to improved culture conditions to expand HSCs in culture for therapeutic applications, and the development of novel therapeutic strategies that promote recovery after bone marrow transplantation. Our results also bear important implications for blood cancers driven by the transformation of normal HSCs, such as chronic myeloid leukaemia.

Funding Notes

UKRI-funded studentships are open to students worldwide and will cover tuition fees at the UK rate, plus a stipend to support living costs and an annual research grant of £5,000 for the first three years of the PhD research. The proportion of international students appointed through the EASTBIO DTP is capped at 30%.  All students must meet the eligibility criteria as outlined in the UKRI guidance on UK, EU and international candidates. This guidance should be read in conjunction with the UKRI Training Grant Terms and Conditions, esp. TGC 5.2 & Annex B.

Apply Now 

EASTBIO How to Apply webpage

• EASTBIO Application
• Equality, Diversity and Inclusion (EDI) survey
• Reference Forms can be downloaded via link above

Please send your completed EASTBIO Application Form and EDI survey along with a copy of your academic transcripts to crm-training@ed.ac.uk before the deadline. 

You should also ensure that two references have been sent to crm-training@ed.ac.uk  by the deadline using the EASTBIO Reference Form.

The EASTBIO team will run a series of 1-hour online sessions in December 2024, open to applicants who have queries about the application process. Please view EASTBIO How to Apply webpage for details. 

Unfortunately due to workload constraints, we cannot consider incomplete applications. 

EASTBIO (College of Science and Engineering) 

Chimeric gastruloids for modelling the genetic and metabolic basis for developmental defects

Applications accepted up to Friday 17th Janaury 2025

1st Supervisor: Prof Valerie Wilson (University of Edinburgh) 

2nd Supervisor: Prof Sally Lowell (The University of Edinburgh)

3rd Supervisor: Dr Linus Schumacher (The University of Edinburgh)

About the Project

In this project you will develop cell-based models of mouse and human development and use them to model developmental disorders.  

Caudal regression syndrome is a rare developmental disorder whose risk is dramatically increased in diabetic pregnancies where glucose is not well-regulated. An overlapping set of defects are caused by partial loss of function of MNX1 (https://omim.org/entry/176450), a gene that is expressed in neuromesodermal progenitors, which generate the elongating head-to-tail axis (doi: 10.1242/dev.180612; 10.1016/j.devcel.2017.01.015). Therefore this spectrum of defects may be due to malfunction of neuromesodermal progenitors which metabolise glucose differently from their differentiated derivatives (doi: 10.1242/dev.201955). However the molecular, cellular, and metabolic basis for these disorders remains unclear.

In our labs we use pluripotent-cell-based models of embryonic development (mouse and human gastruloids) to understand how neuromesodermal progenitors are normally regulated during development. We have developed quantitative approaches for establishing how cell intrinsic factors and local microenvironment work together to orchestrate differentiation and morphogenesis (https://doi.org/10.1038/s44318-024-00154-w).

In this project, you will generate pluripotent mouse and human cell lines harbouring genetic lesions (e.g. Mnx1) and reporters of metabolic states to investigate these metabolic defects. You will use these cells to generate chimeric gastruloids to understand when, where, and how dysregulation of progenitor cells might result in morphological and differentiation defects, and to unpick the role of glucose metabolism in normal and dysregulated development. You will then use mathematical modelling to examine differences in metabolism between progenitors and their derivatives to generate testable predictions about how metabolic regulation could control morphogenesis. 

Funding Notes

UKRI-funded studentships are open to students worldwide and will cover tuition fees at the UK rate, plus a stipend to support living costs and an annual research grant of £5,000 for the first three years of the PhD research. The proportion of international students appointed through the EASTBIO DTP is capped at 30%.  All students must meet the eligibility criteria as outlined in the UKRI guidance on UK, EU and international candidates. This guidance should be read in conjunction with the UKRI Training Grant Terms and Conditions, esp. TGC 5.2 & Annex B.

Application Portal  

Complete our online Application Checklist. From here you can formally apply online. This checklist also provides a link to EASTBIO - how to apply web page. You must follow the Application Checklist and EASTBIO guidance carefully, in particular ensuring you complete all the EASTBIO requirements, and use /upload relevant EASTBIO forms to your online application (as listed below):

• EASTBIO Application
• Equality, Diversity and Inclusion (EDI) survey
• Reference Forms 

(downloaded via  EASTBIO How to Apply webpage)

You should also ensure that two referees have been contacted in advance of the deadline, and provided with the EASTBIO Reference Form.

The EASTBIO team will run a series of 1-hour online sessions in December 2024, open to applicants who have queries about the application process. Please view EASTBIO How to Apply webpage for details. 

Unfortunately due to workload constraints, we cannot consider incomplete applications.

The School of Biological Sciences is committed to Equality & Diversity https://www.ed.ac.uk/biology/equality-and-diversity

EASTBIO (College of Science and Engineering) 

Role Of Mechanosensing In The Development Of Haematopoietic Stem Cells 

Applications accepted up to Friday 17th Janaury 2025

1st Supervisor: Prof Alexander Medvinsky (University of Edinburgh) 

2nd Supervisor: Dr Guillaume Blin (The University of Edinburgh) 

About the Project

Haematopoietic stem cells (HSC) emerge from the endothelium of the embryonic dorsal aorta through the process called endothelial-to-haematopoietic transition (EHT). Mechanical cues generated during embryo morphogenesis can be sensed by cells and drive molecular signalling pathways underlying cell fate choice, organ sizes and tumorigenesis. Accumulated evidence suggests that a key transcriptional regulator of mechanosensing called YAP1 is involved in the regulation of EHT. This project is a part of a broader research programme investigating mechanisms of HSC development and involves collaboration with experts in mechanobiology and bioinformatics.

In this project, human pluripotent embryonic stem cells (hPSCs) will be used to study the role of mechanosensing in EHT. Multicolour reporter hPSC lines will be used to monitor EHT dynamics and coordinated YAP1 behaviour in normal and perturbed conditions. Functional screening of genes associated with YAP1 signalling, cell adhesion and cytoskeletal rearrangements will be performed to study their involvement in EHT. Specific aims are:1) Generation of multi-colour reporter hPSC cell lines based on successful YAP1 reporter generated by us. Live imaging and confocal analysis of reporters’ behaviour during EHT. 2) Investigation of interactive links between mechanosensing and EHT using molecular perturbations and microenvironmental cues.3) Computational modelling of EHT integrating mechanosignalling. Techniques: a) Haematopoietic differentiation of hPSCs; b) CRISPR/Cas9 technology and other molecular biology techniques; c) time-lapse/ confocal microscopy; d) multicolour flow cytometry; e) molecular perturbations using knockdown and overexpression techniques; f) microfabrication of adhesion substrates of different geometry and stiffness; g) computational modelling (collaboration with Dr. Adrien Hallou, Oxford). All aforementioned techniques are broadly used in our labs.

References

(1)    Medvinsky et al. Embryonic origin of the adult hematopoietic system: advances and questions. Development 2011 Vol. 138 ;1017-31(2)    Ivanovs et al., Human haematopoietic stem cell development: from the embryo to the dish. Development 2017 Vol. 144 Issue 13 Pages 2323-2337(3)    Crosse et al., Multi-layered Spatial Transcriptomics Identify Secretory Factors Promoting Human Hematopoietic Stem Cell Development. Cell Stem Cell 2020 Vol. 27 Issue 5 Pages 822-839 e8(4)    Garcia et al., In vitro modelling of anterior primitive streak patterning with hESC reveals the dynamic of WNT and NODAL signalling required to specify notochord progenitors. Development (in press).(5)    Hallou, A. et al., A computational pipeline for spatial mechano-transcriptomics. Nature Methods (in press). (see previous draft: Hallou et al. in BioRxiv).  (6)    Moya, I. and Halder, G. Hippo-YAP/TAZ signalling in organ regeneration and regenerative medicine. Nat Rev Mol Cell Biol 2019 Vol. 20, 211-226 

Funding Notes

UKRI-funded studentships are open to students worldwide and will cover tuition fees at the UK rate, plus a stipend to support living costs and an annual research grant of £5,000 for the first three years of the PhD research. The proportion of international students appointed through the EASTBIO DTP is capped at 30%.  All students must meet the eligibility criteria as outlined in the UKRI guidance on UK, EU and international candidates. This guidance should be read in conjunction with the UKRI Training Grant Terms and Conditions, esp. TGC 5.2 & Annex B.

Application Portal 

Complete our online Application Checklist. From here you can formally apply online. This checklist also provides a link to EASTBIO - how to apply web page. You must follow the Application Checklist and EASTBIO guidance carefully, in particular ensuring you complete all the EASTBIO requirements, and use /upload relevant EASTBIO forms to your online application (as listed below):

• EASTBIO Application
• Equality, Diversity and Inclusion (EDI) survey
• Reference Forms 

(downloaded via  EASTBIO How to Apply webpage)

You should also ensure that two referees have been contacted in advance of the deadline, and provided with the EASTBIO Reference Form.

The EASTBIO team will run a series of 1-hour online sessions in December 2024, open to applicants who have queries about the application process. Please view EASTBIO How to Apply webpage for details. 

Unfortunately due to workload constraints, we cannot consider incomplete applications.

The School of Biological Sciences is committed to Equality & Diversity https://www.ed.ac.uk/biology/equality-and-diversity