Mechanisms linking vascular ageing and excessive bleeding in cardiovascular disease
About the Project
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:
- 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.
- GWAS/ Mendelian randomisation of candidate genes and pathways identified in -omics analyses in CVS patients who experience bleeding.
- 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.
- 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.
Project enquiries to Prof Gavin Murphy gjm19@leicester.ac.uk
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