An integrative mathematical approach to understand how intraplaque angiogenesis and vascular structure impact atherosclerosis and their potential as novel therapeutic targets

Co-supervisor: Prof. Robin Choudhury, Radcliffe Department of Medicine

Co-supervisor: Prof. Claudia Monaco, Nuffield Department of Orthopaedic Rheumatology and Musculoskeletal Sciences

Commercial partner:  Novo Nordisk

Atherosclerosis is a disease of large and medium-sized arteries that is complicated by cardiovascular events, such as myocardial infarction and stroke, which are typically driven by arterial thrombosis. Neovascularisation in the intima and media of the vessel wall is a hallmark of advanced atherosclerotic lesions and accumulating genetic and clinical evidence support that intra-plaque angiogenesis promotes atherosclerosis and plaque destabilisation, rupture or erosion. However, the extent to which microvascular integrity and function change during plaque development is currently unclear. The consequences of changes in vascular structure and function for immune cell infiltration, plaque composition, and stability also remain to be established. Answering these questions via advanced model simulations may ultimately aid in the identification, and subsequent experimental testing, of new mechanisms and targets for therapeutics within atherosclerosis.

This multidisciplinary project will combine mathematical approaches with experimental data to test the hypothesis that microvascular integrity and function influence plaque development by altering immune cell infiltration, plaque composition, and stability.

The main aim of this project is to develop mechanistic mathematical models to understand how intra-plaque angiogenesis and vascular remodelling impact the progression and stability of human atherosclerotic plaques. A secondary project aim is to use the model to explore the potential for targeting angiogenesis and vascular remodelling to treat atherosclerosis.  

Initial work will focus on the development of a mathematical model that couples intra-plaque angiogenesis and vascular remodelling with plaque growth, and is based on our existing mathematical models of angiogenesis and early plaque growth. Through extensive parameter sensitivity analyses, we will use the model to investigate how structural features of the microvasculature impact oxygen levels within atherosclerotic lesions, their infiltration by immune cells and lipid and, hence, the dynamics of their subsequent growth, composition and stability.  We will develop additional models of relevant subcellular signalling pathways to understand how endothelial cell behaviours change in response to microenvironmental cues. By combining these subcellular models with the model of vascular plaque growth, we will assess the potential for manipulating intra-plaque angiogenesis by targeting signalling pathways within endothelial cells to treat atherosclerosis. 

The mathematical models will be informed by, and tested in, tailored lab experiments using existing human in vitro endothelial and smooth muscle cell models within Novo Nordisk (NN) at sites in Denmark, Oxford and Beijing.

This multidisciplinary project aligns naturally with the MRC’s strategic research theme in Population and Systems Medicine and its health focus themes in Global Health and Advanced Therapies: it will use mathematical modelling to deliver new understanding of how angiogenesis and vascular remodelling impact atherosclerosis and then use that knowledge to identify related, novel therapeutic targets.

The project will benefit its participants in multiple ways. It will establish a new multidisciplinary team of theoreticians (Byrne, Baker) and experimentalists (Choudhury, Monaco) that will serve as a foundation for further joint work. The new understanding of a disease relevant mechanism of action is relevant to NN. The partnership will lead to more rapid exploitation of the research findings and, in so doing, bring benefits to the academics and NN.

Apply using course: DPhil in Mathematics