2026-27 Project (Meijles & Carroll & Roberts)
Defining the role of hypoxia-mediated endothelial to mesenchymal transition (EndMT) in maladaptive cardiac remodelling
SUPERVISORY TEAM
Supervisor
Dr Daniel Meijles at City St George’s
School of Health & Medical Sciences, Department of Molecular and Biomedical Sciences
Email: dmeijles@sgul.ac.uk
Co-Supervisor
Dr Veronica Carroll at City St George’s
School of Health & Medical Sciences, Department of Molecular and Biomedical Sciences
Email: vcarroll@citystgeorges.ac.uk
Co-Supervisor
Dr Catherine Roberts at City St George’s
School of Health & Medical Sciences, Department of Molecular and Biomedical Sciences
Email: carobert@sgul.ac.uk
PROJECT SUMMARY
Project Summary
Hypertension affects 1 in 3 people in the UK and is one of the leading causes of cardiovascular disease and heart failure. Despite the availability of numerous anti-hypertensive medications, adequate blood pressure control is achieved in less than 50% of patients. The aims of this PhD studentship are to explore the underlying mechanisms of ischaemia-induced fibrosis that lead to cardiac remodelling, loss of contractility and heart failure. The student will investigate novel genes implicated in matrix remodelling that we have identified in preliminary work, with the aim to identify new treatment approaches for hypertension. The project will use several experimental platforms to include 2D and 3D tissue-specific cellular models, in vivo models using zebrafish and molecular interrogation of murine and human tissue biobanks. The student will be trained in a broad range of cell and molecular biology techniques as well as state-of-the-art imaging modalities.
Project Key Words
hypertension, ischemia, cardiac remodelling, heart failure
MRC LID Themes
- Translational and Implementation Research
- Global Health
Skills
MRC Core Skills
- Whole organism physiology
- Quantitative skills
Skills we expect a student to develop/acquire whilst pursuing this project:
In addition to the transferable skills covered by the graduate school, training in a range of cell and molecular biology, and protein biochemistry techniques focused towards characterising fibrosis and cardiovascular biology will be provided. Students will additionally learn how to perform translational cardiovascular research involving small animal models. Specifically, the student will develop the following skills:
- Design and conduct of scientific experiments.
- Statistical evaluation of quantitative data.
- In-depth understanding of signalling mechanisms controlling cellular cross-talk and remodelling.
- Presentation of scientific data.
- Time-management and organisational abilities.
- Management of written records and cross-referencing of electronic data files.
- Use of computer software for generating research outputs.
Routes
Which route/s are available with this project?
- 1+4 = Yes
- +4 = Yes
Possible Master’s programme options identified by supervisory team for 1+4 applicants:
- City St Georges – MRes Biomedical Science – Clinical Biomedical Research
- City St Georges – MRes Biomedical Science – Infection and Immunity
- City St Georges – MRes Biomedical Science – Molecular Mechanisms of Cancer
- City St Georges – MRes Biomedical Science – Reproduction and Development
- City St Georges – MSc Applied Biomedical Science
- City St Georges – MRes/MSc Translational Medicine
Full-time/Part-time Study
Is this project available for full-time study? Yes
Is this project available for part-time study? Yes
Location & Travel
Students funded through MRC LID are expected to work on site at their primary institution. At a minimum, all students must meet the institutional research degree regulations and expectations about onsite working and under this scheme they may be expected to work onsite (in-person) more frequently. Students may also be required to travel for conferences (up to 3 over the duration of the studentship), and for any required training for research degree study and training. Other travel expectations and opportunities highlighted by the supervisory team are noted below.
Day-to-day work (primary location) for the duration of this research degree project will be at: City St George’s – Tooting campus, London
Travel requirements for this project: None
Eligibility/Requirements
Particular prior educational requirements for a student undertaking this project
- Minimum standard institutional eligibility criteria for doctoral study at City St George’s
- BSc (Hons) in Biological Science (2:1)
Other useful information
- Potential Industrial CASE (iCASE) conversion? = No
- CSG change of supervisory role = The supervisory team may switch roles over the course of the studentship award.
PROJECT IN MORE DETAIL
Scientific description of this research project
Pulmonary and systemic hypertension (PSH) affects 1:3 UK individuals and share adverse cardiac remodelling in disease aetiology. Mechanistically, PSH compromises cardiac function and output, leading to reduced coronary flow, areas of localised myocardial hypoxia and inflammation, and deposition of fibrotic material that typifies end-stage heart failure. Understanding novel cardiac fibrosis regulators, therefore, proffers new therapeutic PSH insight.
Hypoxic remodelling drives microvascular dysfunction. While endothelial cells (ECs) respond to adaptive angiogenic mechanisms, our data shows endothelial-to-mesenchymal transition (EndMT) as a potential source of ventricular fibrosis disrupting angiogenic adaptation in human and murine models. Hypoxia-inducible factors (HIF-1α and HIF-2α) are key meditators of EC dysfunction that initiate the transcriptional response to chronic hypoxia. HIFs and HIF-target genes co-operate with other central pathways that drive inflammation and cellular metabolism, such as mechanistic target of rapamycin (mTOR) signalling. Together, HIFs and mTOR orchestrate cellular changes that promote EndMT and fibrosis. However, how this axis causes EndMT and brings about a pro-fibrotic phenotype in PSH is unknown. Potential candidate genes identified from preliminary experiments include the lysyl hydroxylases (PLODs1-3) and the mTOR regulator, DEPTOR. Thus, the hypothesis for this studentship is that the HIF-inflammo-mTOR-axis causes cardiac fibrosis by driving EC reprogramming via EndMT.
Objectives
i) Establish the functional consequences of hypoxia-mediated EndMT on fibrotic deposition in vitro in 2D and 3D cellular models using the OxyGenie® platform.
ii) Examine HIF-inflammo-mTOR-mediated EndMT and fibrosis in diseased vascular tissue (lungs vs hearts) of human and murine origins.
iii) Define whether HIF-inflammo-mTOR antagonists and genetic manipulation of candidate genes affect EndMT-linked fibrosis in vivo using zebrafish.
Techniques
- In vitro 2D and 3D models with vascular cell cultures to explore EC physiology and transition to a mesenchymal state and to assess collagen deposition vs proliferation/migration assays using quantitative time-lapse imaging in normoxia and hypoxia.
- In vivo zebrafish disease models using isoprenaline-induced heart failure.
- Tissue processing, histology and immunohistochemistry/in situ hybridisation, characterisation for EndMT markers including proximity ligation assay, HCR and confocal imaging.
- Molecular characterisation assays including confocal microscopy, immunoblotting/immunostaining/immunofluroescence, RNA preparation and quantitative PCR techniques, siRNA knock-down and over-expression techniques.
- Genetic (CRISPR Cas9 knockout or mRNA overexpression) in vivo and drug studies using novel HIF-inflammo-mTOR-axis antagonists in vitro and in vivo.
Specialist materials
The applicants have curated biobanks of control and diseased human (lungs and hearts), murine (all organs), and zebrafish, alongside human vascular cells (e.g., cardiac/lung-ECs, cardiac/lung-VSMCs, cardiac-fibroblasts). These biobanks are available to the student and used throughout their project.
Mitigation of risks
Extensive preliminary data shows EndMT drives EC dysfunction and maladaptive tissue remodelling. However, alternative cell types may play a greater role than ECs in transitional reprogramming. As such, other cell types (e.g. pericytes) will also be explored if needed.
Our multi-platform proposal brings together experts in lung & heart (Carroll), cardio-genesis (Roberts) and cardiac (Meijles) biology; each of whom have vast experience in biochemical methods, characterisation of research tissues and cellular models, and laboratories equipped for successful project delivery. Moreover, the student will be supported by the wider research environment, including lab technicians, post-doctoral scientists and other post-graduate students within the department.
Further reading
Relevant preprints and/or open access articles:
(DOI = Digital Object Identifier)
- DOI: 10.5772/67151
- doi.org/10.1038/s41392-023-01652-9
Other pre-application materials: None
Additional information from the supervisory team
The supervisory team has provided a recording for prospective applicants who are interested in their project. This recording should be watched before any discussions begin with the supervisory team.
Meijles & Carroll & Roberts Recording
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