Control of immunity through changes in metabolism-‘immunometabolism,’ if it can be better understood, is recognised as a potential site of intervention to promote healthy ageing (O'Neill et al., 2016); however, existing nonsteroidal anti-inflammatory drugs (NSAIDs) and anti-TNF drugs have shown limited utility in delaying onset of age-related disease. These apparent contradictions may be reconciled if it is recognised that our current notion of ‘inflammation’ encompasses a network of components, some of which favour and some of which detract from healthy ageing. If this new paradigm is correct, selective immunometabolic ‘remodellers’ may have genuine utility in healthy ageing.
Our recent award-winning work in this area has identified for example anti-inflammatory effects of the starvation mimic metformin, even in the absence of diabetes (Cameron et al., 2016). Other starvation mimics such as AICAR, are also understood to remodel inflammation. In cells, preliminary work for this project has established differences in how AICAR and metformin control inflammation and other cell responses. A more robust understanding of these differences is likely to provide new insights into immunometabolic signalling targets but it is unclear yet whether or not such differences are relevant to whole animals. The current studentship will close this gap. The studentship is a multi-disciplinary collaboration between Prof Rory McCrimmon and Dr Graham Rena that will bring together their skills respectively in animal physiology and biochemistry. The project will involve comparing immunometabolic actions of the two drugs in whole animals. The main methods will be to use pharmacological agents and genetic modification in vivo to confirm hypotheses arising from cell experiments.
Conceptually, starvation mimics could act by changing metabolic pathways to alter cell responses or, they may bypass metabolism altogether by altering signalling mechanisms. In vivo, there may be still more complexity, in that the relative contributions of these two aspects may be organ-specific and moreover, may depend on the metabolic state of the organism. This studentship will exploit sophisticated physiological clamping approaches to allow us, for the first time, to establish the dynamic contribution of each mechanism to the immunometabolic action of each drug in vivo. Availability of multi-parallel cytokine assay technologies and RNA-sequencing technologies allow systems-level insights to be developed in in vivo experiments and full training will be provided in each of these required techniques.
The Division of Molecular & Clinical Medicine (MCM) at the University of Dundee provides a highly stimulating academic environment that will strongly support the intellectual and technical demands of the project. MCM has a growing and major focus on translational research, with the scientific thrust ranging from basic science all the way through clinical to population studies. The general facilities, including tissue culture and laboratory facilities are excellent.
Cameron, A.R., Morrison, V., Levin, D., Mohan, M., Forteath, C., Beall, C., McNeilly, A.D., Balfour, D.J.K., Wong, A.K.F., Viollet, B., et al. (2016). Anti-inflammatory effects of metformin irrespective of diabetes status. Circ. Res. 119, 652-665.
O'Neill, L.A.J., Kishton, R.J., and Rathmell, J. (2016). A guide to immunometabolism for immunologists. Nature Reviews Immunology 16, 553-565.