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A personalised assessment of cardiovascular risk: unravelling the link between oxylipidome and retinal microvasculature

Primary Supervisor: Dr Irundika Dias, Life & Health Sciences

Secondary supervisor: Dr Doina Gherghel and Dr Aniko Ekárt

PhD project title: A personalised assessment of cardiovascular risk: unravelling the link between oxylipidome and retinal microvasculature

University of Registration: Aston University

Project outline:

Background

Cardiovascular disease (CVD) is the leading cause of death worldwide and there are an estimated 7 million people living with CVD in the UK. Even though, a range of programmes and initiatives to support prevention, detection and treatment of CVD, most assessment tools based on population estimates, either over- or underestimate risks in >50% of Individuals. Lipids are important signalling molecules, regulating barrier function and inflammation in the vasculature. The lipid environment, interaction with immune cells and local blood flow are key determinants of CVD. We have shown that immune cell behaviour and lipid metabolism in hypercholesterolaemic patients are compromised and display high levels of lipid oxidation. We also demonstrated that dynamic retinal microvascular behaviour, a measure of the vascular endothelial function, is unique to each individual and their age group and each individual’s vascular risk factors or existing pathologies. Following up from these observations, we developed a short, non-invasive vascular imaging approach combined with computer modelling to help predict cardiovascular risk. However, we do not know how individual (oxy)lipidome contribute to defining future vascular risk. Our aim is to address this knowledge gap in biochemistry and physiology of retinal vasculature to improve CVD risk assessment. We will take a multidisciplinary approach to test the hypothesis that the integration of (oxy)lipidome and individual vascular signature is sensitive enough to aid early prediction and develop personalised interventions to cardiovascular disease.

Objectives

  1. To define the biochemistry and physiology of circulating (oxy)lipids using our comprehensive LC/MS methods.
  2. To ascertain the impact of the (oxy)lipodome on dynamic microvascular parameters.
  3. Integrate lipidomics and microvascular functional for building robust models to identify CVD risk.

Methods

The Vascular Imaging Research Laboratory at Aston University has already collected retinal vascular data from over 300 volunteers over the past five years, banked blood samples from a subset of these patients (n=50) will be analysed in this study (Ethical approval is in place for biomarker analysis). Plasma lipids will be extracted using established method in our laboratory. As plasma contains a complex lipid pool, to achieve separation between lipid classes, samples will be analysed by reverse-phase chromatography coupled to mass spectrometry (LC-MS/MS). We will explore the underpinning mechanisms as protein carbonyl and nitrates (nitric oxide and reactive oxygen species) and cytokines analysis. The complex analysis of lipid species will be accomplish by using software tools such as Analyst®, PeakView® and MetAlign. Such information is extremely time consuming to manually interrogate but will provide a future resource for retrospective interrogation in relation to retinal vascular changes.

We will incorporate (oxy)lipidome data to our already established models using machine learning techniques, which predicts individual CVD risk based on retinal microvascular function parameters. The dynamic nature of the retinal vascular response assessed in these very diverse individuals will then be used to develop and validate a method for building robust models for individuals with CVD risk.

Proposed project is a multidisciplinary research project that involved biochemical analysis, computer science techniques, vascular imaging, health informatics, and project management under the supervision of Dr Dias, Dr Gherghel and Dr Ekárt.

References:

  1. Irundika Dias, Ivana Milic, Gregory Y H Lip, Andrew Devitt, Maria C Polidori, Helen R Griffiths. Simvastatin reduces circulating oxysterol levels in men with hypercholesterolemia. Redox Biology, 2018. Jun; 16: 139–145.
  2. Swathi Seshadri, Stephanie Mroczkowska, Lu Qin, Sunni Patel, Anikó Ekárt and Doina Gherghel. “Systemic circulatory influences on retinalmicrovascular function in middle-age individuals with low to moderate cardiovascular risk”. In: Acta ophthalmologica 93.4 (2015).

BBSRC Strategic Research Priority: Understanding the Rules of Life: Structural Biology

Techniques that will be undertaken during the project:

  • Liquid chromatography
  • Mass spectrometry
  • Statistical analysis
  • Computational modelling

Contact: Dr Irundika Dias, Aston University