PhD Studentship in Cardiovascular Sciences

The College of Life Sciences is offering one studentship from two projects within Cardiovascular Sciences.

Supervisors for both projects:  

• Professor Gavin Murphy gjm19@leicester.ac.uk
• Professor Veryan Codd
• Dr Tom Webb

Project 1 

Understanding the mechanisms linking myocardial ageing and the type of cell death in people with and without multimorbidity.

Rationale: Current myocardial protection strategies are focused on the prevention of necrosis and apoptosis, and not other important mechanisms of injury such as ferroptosis or  pyroptosis. Rates of myocardial injury after cardiac surgery have remained unchanged for decades. Our research suggest that baseline inflammageing in the myocardium in people with multimorbidity determines the type of injury, and therefore the best myocardial protection strategy.
Hypothesis: The type of cellular injury following cardiac surgery is determined by the baseline ageing phenotype. Different baseline phenotypes will require different myocardial protection strategies.
Methods: 

• 1. Proteolipidomics analyses of myocardial biopsies before and after ischaemia reperfusion injury in cardiac surgery patients. Informatics analyses will establish the relations between baseline phenotype and mechanism of injury.
• 2. GWAS/ Mendelian randomisation of candidate genes and pathways identified in -omics analyses in CVS patients who experience death or myocardial injury after surgery and type 2 MI.
• 3. Proteomics analyses of in vitro models of cardiomyocyte ageing and the cellular injury arising from IRI to determine the relationship with different stages of ageing and the cell response to injury. Causality of key pathways will be determined using established knock-in or knock out methods. A proteomics signature of different ,mechanisms of death will be developed.
• 4. Validation of a protein signature of different forms of cell death in vivo using stored plasma samples from cardiac surgery patients.
  Value of Results: This research will offer new insights into the failure of existing organ protection strategies to reduce myocardial injury and present a rationale of a precision medicine approach to myocardial protection.

References
1. doi: https://doi.org/10.1101/2024.04.05.24305379 
2. doi: 10.1038/s41588-024-01884-7. PMID: 39192095
3. doi: 10.1038/s41588-021-00944-6. PMID: 34611362
4. doi: 10.1111/trf.18399. PMID: 41110116
5. doi: 10.1002/rth2.12024. PMID: 30046693

Project 2

Mechanisms linking vascular ageing and excessive bleeding in cardiovascular disease

Rationale: Excessive bleeding complicates 25% of cardiac surgery procedures. Our research suggests that vascular ageing and endothelial mesenchymal transition are important mechanisms underlying bleeding. Similar mechanisms are implicated in bleeding associated with multiple cardiac syndromes including acute coronary syndrome, stroke and atrial fibrillation.
Hypothesis: Identification of causal mechanisms underlying the association between vascular ageing and excess bleeding will allow the identification of diagnostic tests and targeted treatments.
Methods:

1. Integrated -omics analyses of vascular ageing in bleeding and non-bleeding phenotypes using snRNAseq, snATACseq, deconvoluted bulk seq and metabolomics of vascular and myocardial biopsies collected at surgery.

2. GWAS/ Mendelian randomisation of candidate genes and pathways identified in -omics analyses in CVS patients who experience bleeding.

3. Plasma proteomics of the bleeding phenotype, development of a vascular ageing/ bleeding protein panel using AI (with the VG Biomarker facility) with validation in the COPTIC cohort.

4. Development of an in-vitro model of endothelial dysfunction (with Oxford) associated with the bleeding phenotype and modification of target genes using knock-in/ knock out methods.

Value of the results: This project will identify new mechanisms  underlying excessive bleeding in people with cardiovascular disease as well as novel diagnostic tests for these processes and potential treatments for evaluation in clinical trials.
 
References
1. doi: https://doi.org/10.1101/2024.04.05.24305379 
2. doi: 10.1038/s41588-024-01884-7. PMID: 39192095
3. doi: 10.1038/s41588-021-00944-6. PMID: 34611362
4. doi: 10.1111/trf.18399. PMID: 41110116
5. doi: 10.1002/rth2.12024. PMID: 30046693 

Please select your preferred project and include:

Professor Murphy and your preferred project title on your online application form under the section 'supervisors/project' Follow the application advice under How to Apply below before submitting your application using the link at the bottom of the web page.