The North-East Scotland (NES) Diabetes and Cardiovascular Research Alliance Masters Training Programme (MTP) in cardiovascular and diabetes medicine is an exciting new programme that will expand interdisciplinary cardiovascular and diabetes research between the University of Aberdeen and the University of Dundee.
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Determining the function of a novel mutation in beta-arrestin1 in the treatment of type 2 diabetes
Type-2 diabetes (T2D) is a major burden on the NHS and society, and developing more effective therapeutics is key in treating this disorder. As part of the DIabetes REsearCh on patient straTification (DIRECT) Consortium, we performed meta-GWAS on glycaemic response on people with T2D that were treated with Glucagon-like peptide receptor (GLP1R) targeting drugs. This revealed a novel mutation that corresponded to an improved response. This mutation (T370M) was found in the gene encoding beta-arrestin1, a critical protein in the regulation and signalling of the G-protein-coupled receptor family of proteins, of which GLP1R is a member. At the molecular level, GLP1R drugs activate the receptor to intiate signalling cascades leading to insulin release, but also drive association with regulatory proteins, including beta-arrestins. Arrestins limit signalling of GLP1R and intiate endocytic trafficking; and also stimulate unique signaling events. Although arrestins are important for appropriate GLP1R function it is unknown how this novel mutation would enhance responsiveness of the GLP1R, a question that will be addressed in this MSc project. We hypothesise that the arrestin mutation will maintain GLP1R levels on the cell surface and enhance signalling responses. This will be investigated using heterologous expression systems to express the GLP1R and determine its activation profile. This includes G-protein signalling, the desensitisation, internalization and postendocytic recovery. This will be measured by a combination of biochemical techniques, flow cytometry, imaging and genetic biosensors. Critically,
we will utilise a cell line that does not express endogenous arrestins, to allow selective recapitulation with either wild-type or the T370M mutated vesion of arrestin. Finally, a known phenomonom amongst GPCRs is that different ligands can promote differing levels of arrestin recruitment, known as ligand bias. We will test if different ligands (GLP1, liraglutide, exendin-4) are effected to the same extent by the arrestin mutant. These findings have the potential to influence personalised medicine.
Informal project enquiries are encouraged. Please contact Dr James Hislop ([Email Address Removed]) for more information
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This opportunity to achieve an MSc by Research is part of a flagship collaborative programme between the two universities. Based either in Aberdeen or Dundee but with cross-institutional training opportunities, students will be embedded in vibrant multidisciplinary research teams with a mix of cardiovascular/diabetes clinicians and scientists. Excellent research training opportunities are provided, including MTP specific training events, and more general training and educational activities in the universities, highlighted for example by the newly established Doctoral Academy in Dundee.
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ENTRY REQUIREMENTS & ELIGIBILITY
Applicants must possess or be expected to possess by the time of starting the MSc, at least one of the following:
- First class, or upper second-class UK Honours Degree (or international equivalent) in a relevant scientific discipline.
- Postgraduate Masters degree in a relevant scientific discipline, or equivalent.
International applicants may apply for this studentship but will have to find additional funding to cover the difference between overseas and home fees (~£18,000 per annum).
International applicants receiving a funded offer of study covering UK fees only will be asked to provide evidence that this fee difference can be met.
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APPLICATION PROCEDURE
- Full application instructions and further information can be found by visiting the following link: Masters Training Programme
- CV's submitted directly through a FindAPhD enquiry WILL NOT be considered.
- If you have further questions, please email [Email Address Removed]
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