Identification of novel glucose-dependent alterations responsible for vascular dysfunction in Type 2 diabetes

Diabetes is a growing global healthcare problem. The majority of people living with diabetes have Type 2 diabetes mellitus (T2DM), characterised by a resistance of the body to the action of insulin. Clinical data suggest that more than 70% of these patients will die of cardiovascular diseases (CVDs) including heart attack and stroke. Coronary artery bypass graft (CABG) surgery, which typically utilises autologous saphenous vein, is the preferred revascularisation option for improving coronary blood flow in patients with diabetes. However T2DM may increase patient vulnerability to vein graft failure following CABG, a phenomenon which may arise from specific alterations in human saphenous vein smooth muscle cell (HSV-SMC) phenotype that trigger vascular thickening and re-modelling observed in veins from patients with T2DM. We propose that protein O-GlcNAcylation, a glucose-dependent modification that links diabetes with protein function, alters HSV-SMC function through post-translational modification of key proteins.

Using cutting edge biochemical and molecular pharmacological approaches the student will

A) Apply new biochemical tools to specifically isolate O-GlcNAcylated proteins from HSV-SMCs
B) Use mass spectrometry to identify O-GlcNAcylated proteins specifically enriched in HSV-SMCs from T2DM patients
C) Use biochemical and genetic approaches to validate and characterise the effects of target protein O-GlcNAcylation on HSV-SMC function.

The aim of this PhD project is to apply tools and expertise available in the supervisors’ laboratories to test the hypothesis that protein O-GlcNAcylation links altered HSV-SMC function with the increased risk of vein graft failure seen in T2DM patients. To achieve this, the student will pursue an integrated programme of work that brings together the complementary expertise and track records of the supervisors in the study of protein biochemistry and molecular biology, HSV-SMC function and T2DM, to identify new therapeutic targets to reduce the vascular re-modelling responsible for vein graft failure in T2DM patients.