Investigating vascular cell behaviour in diabetes-induced atherosclerotic plaques

Atherosclerosis is the leading cause of premature mortality around the world. Fat deposition within arteries forms atherosclerotic plaques, which lead to heart attack and stroke when these plaques rupture. Diabetes is one of many risk factors that are known to accelerate the onset of atherosclerosis and worsen patient outcome. In fact, diabetic patients make up 20% of all cardiovascular mortalities, and heart attacks are responsible for the majority of mortalities in diabetic patients. Thus, there is a dire need to better understand the links between these two diseases and establish better therapeutic outcomes. Colchicine is the first anti-inflammatory therapy to be FDA approved, but its mechanisms of action are poorly understood.

Vascular cells within the plaque undergo complex behaviours that likely contribute to difficulties in disease treatment. Smooth muscle cells, endothelial cells, and macrophages make up a large majority of cells within the plaque. All of these cells are capable of a degree of trans-differentiation, allowing them to convert into protective or deleterious phenotypes within the plaque. However, how the hyperglycaemic diabetes microenvironment influences these changes in cell phenotype is unclear.

The aim of this project is to better understand how the diabetic microenvironment influences vascular cell trans-differentiation within the plaque. The group will utilise specialised transgenic mouse models that allow the fluorescent labelling of cells and the tracking of their fate during disease pathogenesis. Combining these fluorescent labels with immunofluorescent staining and confocal microscopy will enable the group to identify how vascular cells trans-differentiate. These in vivo techniques will be supplemented with cell culture, qPCR and other in vitro techniques. Identifying how vascular cells behave within diabetic plaques will be a step towards more targeted medicine that can influence the behaviour of single cells.

Aim 1: To investigate how the diabetic microenvironment influences trans-differentiation of vascular cells

Aim 2: To identify potential therapeutic targets or pathways that regulate vascular cell behaviour in the diabetic plaque microenvironment

This study will elucidate how diabetes-induced metabolic changes drive vascular cell plasticity and plaque instability. Identifying key molecular and cellular mechanisms of vascular cell trans-differentiation will help to treat high-risk diabetic plaques. These insights will enable development of targeted therapies that modulate specific vascular cell phenotypes to stabilize plaques. Ultimately, this work aims to improve therapeutic outcomes and reduce cardiovascular mortality in diabetic patients.

Murine models of diabetes and atherosclerosis, lineage tracing and clonal analysis, in vitro cell culture, in vivo mouse models, molecular biology, confocal microscopy and RNA-sequencing.