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Interdisciplinary investigation of the role of amino acids in immunometabolic responses to metformin in human cells


School of Medicine

About the Project

There is overwhelming evidence that inflammation contributes to the development of cardiovascular disease (CVD) but counterbalancing this is evidence from meta-analysis of randomised control trials that many existing anti-inflammatory drugs, such as COX2 inhibitors and anti-TNF drugs, tend if anything to exacerbate risk of CVD. If inflammation is to be targeted successfully in CVD, new paradigms of drug action and new approaches to patient selection need to be generated. Our recent work has been on metformin, which in observational studies also reduces risk of CVD. Our work in this area has established that anti-inflammatory effects of metformin are exerted irrespective of diabetes status [1, 2], through poorly understood ‘immunometabolic’ mechanisms that are different from existing anti-inflammatory drugs and which we have recently found are accompanied by changes in amino acid homeostasis. Better understanding of these effects is likely to have a high-impact, by supporting better stratification and targeting of repurposing trials of metformin in non-diabetic CVD [1]. To ensure relevance to human disease, it is desirable to extend our studies from rodent-derived cells to include human-derived cells. To do this, the student will identify and then use a suitable human cell model to investigate the relationship between amino acid metabolism and immune effects of the drug. This will include evaluation of immortalised cell lines, such as U-937, HL-60 or THP1, to identify combinations of cells/ stimuli suitable for further study. Combination of data from human cell studies with (mouse) knockout cells from our network of collaborators and with biomarkers in human plasma stored from previous clinical trials, as well as exploitation of state-of-the-art patient databases, provides the student with an outstanding platform to establish high-impact translational cross-validation of clinical observations with cell/molecular findings, as demonstrated in our highly interdisciplinary recent work [1, 2].

For informal enquiries about the project, contact Dr Graham Rena ()
For general enquiries about the University of Dundee, contact


QUALIFICATIONS
Applicants must have obtained, or expect to obtain, a first or 2.1 UK honours degree, or equivalent for degrees obtained outside the UK in a relevant discipline.

English language requirement: IELTS (Academic) score must be at least 6.5 (with not less than 5.5 in each of the four components). Other, equivalent qualifications will be accepted. Full details of the University’s English language requirements are available online: http://www.dundee.ac.uk/guides/english-language-requirements.


APPLICATION PROCESS

Step 1: Email Dr Graham Rena () to (1) send a copy of your CV and (2) discuss your potential application and any practicalities (e.g. suitable start date).

Step 2: After discussion with Dr Rena, formal applications can be made via UCAS Postgraduate. When applying, please follow the instructions below:

Apply for the Doctor of Philosophy (PhD) degree in Medicine: https://digital.ucas.com/coursedisplay/courses/87c1cea2-d3ca-455b-a159-9c89bb825b0d. Select the start date and study mode (full-time/part-time) agreed with the lead supervisor.

In the ‘provider questions’ section of the application form:
- Write the project title and ‘FindAPhD.com’ in the ‘if your application is in response to an advertisement’ box;
- Write the lead supervisor’s name and give brief details of your previous contact with them in the ‘previous contact with the University of Dundee’ box.

In the ‘personal statement’ section of the application form, outline your suitability for the project selected.

Funding Notes

There is no funding attached to this project. The successful applicant will be expected to provide the funding for tuition fees and living expenses, via external sponsorship or self-funding.

References

1. Rena, G. and C.C. Lang, Circulation 2018. accepted for publication DOI: 10.1161/CIRCULATIONAHA.117.031735.
2. Cameron, A.R., et al., Circ. Res., 2016. 119: p. 652-665.

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