Understanding the mechanisms linking myocardial ageing and the type of cell death in people with and without multimorbidity.
About the Project
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.
Project enquiries to Prof Gavin Murphy gjm19@leicester.ac.uk
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