Supervisors: Professor Ruth Andrew, Professor Jonathan Fallowfield, Professor Scott Webster
Project Description:
Life-style factors influence healthy ageing and dietary choices can positively or negatively affect health. The low fat Mediterranean diet is anti-oxidant and believed beneficial for health, whereas high fat “Western diet” precedes health decline. Body mass index is increasing worldwide, linked to increased risk of many diseases, including diabetes and fatty liver disease, but individual risk is not uniform, When challenged with a fatty diet, the body stores this “ectopically” e.g. in liver. This process is initially benign, but beyond a certain level and in certain individuals, it triggers irreversible liver fibrosis and ultimately hepatocellular carcinoma. Biomarkers of health status are highly valuable in allowing us to improve the healthspan of at risk individuals.
Metabolomics provides a fingerprint of personal biochemical status; lipidomics is a subfield, categorising the very many endogenous bioactive lipids regulating metabolism. Lipidomic analysis is most commonly conducted in blood, easy to sample and with potential for health screening. However the circulating lipidome may not reflect the tissue environment. When liver health starts to decline, zonal changes occur with healthy and at-risk tissue co-existing side-by-side. Therefore the lipidomic signature of the liver must be collated in a spatial manner to assign a healthy profile. This studentship will develop mass spectrometry imaging (MSI) to spatially profile lipids in liver and how they respond to dietary fats.
Hypothesis
Diets with varying fat content will differentially affect the hepatic lipidomic. Identification of a lipidomic signature by MSI will reveal biochemical pathways changing with dietary fats, and identify pathways useful for assessing liver health
Project Plan
Initially, the student will establish MSI to sample lipids from liver sections of mouse, rat and human. Sampling modes will be compared (DESI, MALDI ionisation). The profile of lipids in each modality will be collated and species identified through alignment with lipidomic databases e.g. Lipid maps.
Next we will study the hepatic lipidome of mouse models representative of healthy animals and study the effect of a Western diet by varying the fat content and type (e.g. polyunsaturated fat vs monounsaturated). A workflow will be established whereby key components will be identified and those differing between diets identified by multivariate statistics. Key Lipid classes will be confirmed by tandem MS. Image analysis methods for co-localising histological and lipidomic features will be developed. The changes in the lipidome with the duration of diet will be compared and benchmarked against extremes (healthy versus diseased steatotic liver) to identify early biomarkers of dietary insult.
Findings in rodent models will ultimately be translated to human liver biopsies from a well characterised biobank.
Research Training
The student will receive interdisciplinary training in a broad range of methods including: a) in vivo and in vitro studies using liver tissue from animal models and humans b) lipidomics by bioanalytical MS c) multi-variate statistical analysis of lipidomic datasets, involving interfacing with online databases (d) co-registration and image analysis of histological features. Studies will be conducted in well-funded laboratories within the Queen’s Medical Research Institute which are fully equipped for the proposed experiments.
References:
1) Khan, Andrew (2018) MSI of lipids, Current and emerging technologies in lipidomics, Royal Society of Chemistry, London, In Press.
2) Iredale, Pellicoro, Fallowfield (2017) Liver Fibrosis: Understanding the dynamics of bidirectional wound repair to inform the design of markers and therapies. Dig Dis 2017;35:310-313.
3) Cobice et al (2017) Quantification of 11β-HSD1 kinetics and pharmacodynamic effects of inhibitors in brain using MSI and stable-isotope tracers in mice. Biochem Pharm. 148:88-99.
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