Novel Gene Targets to Treat Obesity, Type-2 Diabetes and Cardiovascular Disease

This PhD studentship will be undertaken within the recently established Aberdeen Cardiovascular & Diabetes Centre (https://www.abdn.ac.uk/acdc) which will provide the successful applicant with excellent training and support in all aspects of cardiovascular disease and diabetes.

This project will use multiple cutting-edge approaches to validate and characterise novel gene targets of Fenretinide, vitamin A related drug. These novel genes are likely to be involved in the development of metabolic disease, so this project will identify potential new targets for the future treatment of metabolic diseases thereby obesity, type-2 diabetes and cardiovascular disease, in humans.

We previously reported that a synthetic retinoid drug, Fenretinide, can activate retinoic acid signalling and block the accumulation of ceramide in adipose tissue and liver and thereby inhibit obesity and type-2 diabetes in mice. We have now performed next-generation sequencing on Fenretinide treated samples and identified hundreds of novel gene targets. For example, Fibroblast growth factor 21 (FGF21), an important regulator of glucose and lipid homeostasis, was the most downregulated hepatic gene (Morrice et al 2017, Scientific Reports). We now hypothesise that novel gene targets of Fenretinide may reveal important new insights in the action of Fenretinide and may reveal further therapeutic strategies to treat obesity, type-2 diabetes and cardiovascular disease.

This project will use multiple cutting-edge approaches to validate and characterise novel gene targets of Fenretinide and test these experimentally in a variety of model systems. The project will offer opportunities to become skilled in using a range of molecular techniques including western blotting, qPCR and cell signalling. In diabetes and atherosclerosis mouse models, fed high-fat cholesterol diet, you will examine the role of these genes and nutrition on food intake/appetite, body weight, adiposity by magnetic resonance technology, glucose and lipid metabolism, insulin sensitivity and vascular function of isolated arteries. Moreover, you will measure the change in tissues, lipids and metabolites by liquid-chromatography and mass spectrometry.

Finally, you will get the opportunity to interact with colleagues in the exciting new Aberdeen Cardiovascular & Diabetes Centre to develop the project into innovative directions. Overall the training obtained in this PhD programme will be multidisciplinary, working with medical bio-scientists with expertise in the adipose-liver-brain axis and NHS clinicians to maximise the potential impact on human health.