PhD Research Studentships
Unravelling the hypertensive pressure dependent nuclear mechanosignalling, as driver for atherosclerosis
| Supervisor: | Thomas ISKRATSCH |
| Apply by: | 29 January 2025 |
| Start in: | September (Semester 1) |
Description
Background:
Changes to the vascular smooth muscle cell (VSMC) phenotype is a critical step in many cardiovascular diseases, including atherosclerosis. The altered migratory behavior, extracellular matrix (ECM) secretion, or ECM degradation functions have a severe impact on the arterial wall organization and integrity. Our previous work identified that phenotypic switching can be triggered through pathological mechanical stimuli (especially hypertensive pressure), leading to a transition to a foam-cell like phenotype1-3. Within minutes, VSMC become filled with lipid droplets and alter their cell morphology and protein expression pattern. However, it remains unclear how the formation of lipid droplets is linked to the overall phenotypic changes such as an altered transcription profile, or cellular function - and subsequent disease processes.
Hypothesis: Hypertensive blood pressure leads to altered lipid balance in the nuclear membrane, changes to nuclear mechanics and transcriptional profiles
We hypothesise that pathological mechanical stimuli affect the phenotypic switching of vascular smooth muscle cells. We further propose that the mechano-sensitive formation of lipid droplets is linked to a removal of phospho-lipids from the nuclear membrane, resulting in a change in nuclear viscoelasticity and altered dynamics of transcription factor shuttling through the nuclear pores. This ultimately leads to changing transcription profiles, VSMC function and atherosclerotic disease progression.
Aims and main methodologies:
This project will analyse mechanosensitive lipid droplet formation, changes to nuclear lipids and nuclear mechanics, as well as dynamics of transcription factor shuttling, whereby all experimental protocols are established. The project will combine in vitro experiments, using primary or iPSC derived VSMCs, ex-vivo artery perfusion and in vivo experiments. The student will be trained in state-of-the-art microscopy (super-resolution and optogenetics) and cell mechanical measurements to analyse transcription factor shuttling and lipid dynamics. This will be complemented with omics experiments (transcriptomics, lipidomics,...).
The student will be part of a multidisciplinary team composed of bioengineers, cell biologists and cardiovascular researchers who will train and guide the student throughout all aspects of the project.
1st Supervisor: Prof Thomas Iskratsch, Professor in Cardiovascular Mechanobiology and Bioengineering, School of Engineering and Materials Science
2nd Supervisor: Prof Qingzhong Xiao, Professor of Stem Cell and Cardiovascular Disease, The William Harvey Research Institute
Reference:
1 Swiatlowska, P. et al. Pressure and stiffness sensing together regulate vascular smooth muscle cell phenotype switching. Sci Adv 8, eabm3471 (2022). https://doi.org:10.1126/sciadv.abm3471
2 Faleeva, M. et al. Sox9 Accelerates Vascular Ageing by Regulating Extracellular Matrix Composition and Stiffness. Circ Res 0 (2024). https://doi.org:10.1161/CIRCRESAHA.123.323365
3 Swiatlowska, P. et al. Hypertensive Pressure Mechanosensing Alone Triggers Lipid Droplet Accumulation and Transdifferentiation of Vascular Smooth Muscle Cells to Foam Cells. Adv Sci (Weinh) 11, e2308686 (2024). https://doi.org:10.1002/advs.202308686
Funding
Funded by: China Scholarship CouncilCandidate will need to secure a CSC scholarship.
Under the scheme, Queen Mary will provide scholarships to cover all tuition fees, whilst the CSC will provide living expenses and one return flight ticket to successful applicants.
Eligibility
- The minimum requirement for this studentship opportunity is a good honours degree (minimum 2(i) honours or equivalent) or MSc/MRes in a relevant discipline.
- If English is not your first language, you will require a valid English certificate equivalent to IELTS 6.5+ overall with a minimum score of minimum score of 6.0 in each of Writing, Listening, Reading and Speaking).
- Candidates are expected to start in September (Semester 1).
Contact
For informal enquiries about this opportunity, please contact Thomas ISKRATSCH.
Apply
Start an application for this studentship and for entry onto the PhD Medical Engineering full-time programme (Semester 1 / September start):
Please be sure to quote the reference "SEMS-PHD-629" to associate your application with this studentship opportunity.
| Related website: | https://www.iskratschlab.com | |
| SEMS Research Centre: | ||
| Keywords: | Biophysics, Cell Biology, Molecular Biology, Bioengineering, Biomedical Engineering |