Additional Supervisor: Prof Julian Dow [University of Glasgow]
Background
Obesity levels are rising rapidly around the world and are a major risk factor for diseases such as Type 2 diabetes, cancers and recently, COVID-19. Adipose tissue expansion and dysfunction plays a critical role in the pathophysiology of obesity and associated diseases. There is increasing evidence that genetic factors controlling adipose tissue function are critical determinants in the risk of developing metabolically healthy or unhealthy obesity. A deeper understanding of how these genes affect adipose tissue physiology and metabolism will inform human studies and contribute to the development of strategies to tackle obesity and associated disorders.
To identify genetic factors affecting adipose physiology, we have (i) leveraged genome-wide association studies on human obesity to identify novel genes regulating adipose expansion, and (ii) cross-referenced these candidate genes with metabolically healthy or unhealthy obesity. These genes represent potential therapeutic targets for treating obesity but their role in regulating adipose tissue metabolism is unknown.
In this PhD project, we will use the highly tractable Drosophila model system to gain a mechanistic understanding of how some of these candidate genes regulate adipose tissue metabolism. Drosophila melanogaster is a powerful genetic model that has provided vital insights into fundamental biology for over a century, including the identification of key signalling pathways (such as Wnt, RAS, Hedgehog, and Notch). Despite its evolutionary distance, it has well-conserved metabolic and signalling pathways, analogous organ systems, and orthologs for 75% of all know human-disease related genes. It has an extensive genetic toolkit with loss and gain of function lines targeting almost every gene. Very importantly, these studies will be carried out in vivo in Drosophila which will be of particular benefit as obesity is a systemic disorder.
Using the extensive genetic toolkit available in Drosophila that allows spatial and temporal control of gene expression, we will specifically manipulate Drosophila orthologs of these candidate genes in the adipose tissue at defined developmental stages. To understand how these candidate genes affect adipose metabolism, we will then carry out specialized metabolomic analysis.
Metabolomic analysis will provide a comprehensive measurement of all small molecules, known as metabolites, in the adipose tissue. Metabolomics is a powerful approach for precision medicine because it will provide a accurate representation of the underlying biochemical activity of the adipose tissue. Results obtained from the metabolomic analysis will then help carry out genetic interaction studies in Drosophila with other components of the metabolic pathways identified through the analysis. This will provide a deeper understanding of how candidate obesity-linked genes under study are disrupting adipose metabolism and contributing to the unhealthy effects of obesity.
We will use a variety of methodological approaches in this project including: Drosophila genetic experiments, micro-dissections, liquid chromatography-mass spectrometry protocols, and metabolomic analysis.
The supervisor team has extensive experience and expertise in metablomics, studying the Drosophila adipose tissue, and utilising human genetics to model obesity-linked genes. Members of the supervisory team developed the comprehensive tissue-specific metabolomics resource for Drosophila: FlyMet – which is the authoritative metabolomic tissue ‘atlas’ of Drosophila.
Q&A Session
If you have any questions regarding this project, you are invited to attend a Q&A session hosted by the Supervisor(s) on 8th December at 3pm via Microsoft Teams. Click here to join the meeting. If you get an error message when accessing the link, please try a different device.
About the Programme
This MRC programme is joint between the Universities of Edinburgh and Glasgow. You will be registered at the host institution of the primary supervisor detailed in your project selection.
All applications should be made via the University of Edinburgh, irrespective of project location. For those applying to a University of Glasgow project, your application along with any supporting documents will be shared with University of Glasgow.
Please note, you must apply to one of the projects and you must contact the primary supervisor prior to making your application. Additional information on the application process is available from the following link:
https://www.ed.ac.uk/usher/precision-medicine/app-process-eligibility-criteria
For more information about Precision Medicine visit:
http://www.ed.ac.uk/usher/precision-medicine
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