MSc by Research: Regulation of microglial phenotypes by adenosine and in contribution to ageing in the brain

Microglia are the major innate immune cells in the central nervous system and are required for the response to invading pathogens, removal of damaged or apoptotic cells and also contributing to neuronal development via synaptic pruning.  To achieve these diverse functions, microglia must be able to adopt a spectrum of pro- and anti-inflammatory phenotypes.  The balance between the phenotypes is affected by aging, with microglia from older individuals displaying a greater propensity for an inflammatroy phenotype.  This in turn may promote age-related pathologies in the CNS.  The factors which control the polarisation of microglial phenotypes are however not well understood.  This project will seek to understand the factors controlling microglial polarisation and how these impact on processes in healthy aging and neurodegeneration. 

In the peripheral immune system, macrophages play a similar role to microglia in the CNS.  Anti-inflammatory phenotypes in macrophages are regulated by the SIK kinase family, which are in turn regulated downstream of G protein coupled receptors that activate cAMP signalling, such as the prostaglandin E2 (PGE2) receptors EP2 and 4.   Multiple isoforms of the PGE2 receptor exist and the effects of PGE2 are dependent on the receptor isoform expressed by the cell; EP2 and EP4 activate cAMP signalling while EP3 inhibits due to differential use of Galpha subunits.  In the proposed project we will examine the role that the SIK pathway plays in regulating microglial function downstream of PGE2, which has immunomodulatory effects in the CNS, and adenosine, which has roles in both neurotransmission and immunomodulation as well as potential links to ageing.  Similar to PGE2, adenosine acts via receptors that are in the GPCR family, and like PGE2 receptors different adenosine receptor isoforms have differential effects on cAMP signalling.  To address which receptor isoform is critical, synthetic agonists or antagonists for specific PGE2 or adenosine receptor isoforms will be used, and differences in isoform expression and utilization in microglia from young and aged mice will be examined.  High resolution proteomics using sate of the art mass spectrometry will be used to examine the effects of PGE2 and adenosine on proteome remodelling in microglia, and this will be linked to functional assays to determine the inflammatory phenotype of the cells.  Finally to extend the studies into humans, human iPS cell derived microglia will be analysed.   

Together these approaches will enhance our understanding of how microglial function is controlled during ageing. The project will provide training in a range of techniques including mass spectrometry, bioinformatics and stem cell culture. 

Please see our website for further details on the programme:

Life Sciences MSc by Research MSc by Research (Postgraduate) : Study : University of Dundee

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