Postgraduate research opportunities

Does proteinase-activated receptor 2 (PAR2) activation play a key role in depression?

Research group: Neuroscience & Mental Health Key words: proteinase-activated receptor 2, inflammation, cytokines, major depressive disorder, treatment-resistant depression.

Number of places

1

Opens

5 March 2020

Duration

36 Months

Eligibility

Applicants should possess or be about to obtain a 1st class or 2:1 Honours degree or equivalent in a relevant discipline such as immunology, pharmacology, neuroscience or equivalent. This project is suitable for fully funded, self funded and our PhD Plus Programme

Receipt of satisfactory references.

IELTS 6.5 or equivalent.

Project Details

Four proteinase-activated receptors (PARs1-4) are G protein-coupled receptors (GPCR) that have a novel activation mechanism and have been implicated in various inflammation-related diseases in both the periphery and central nervous system (CNS)1.  We have previously investigated the role of one PAR subtype, PAR2, in CNS function revealing that its activation modulates neuronal excitability2, is neuroprotective3 and plays a role in sickness behaviour4.  We have extended these findings and now have novel data indicating that PAR2 activation leads to depression-like behaviour in mice.  Importantly, this behavioural phenotype is associated with inflammatory changes observed in patients suffering from major depressive disorder (MDD) and treatment-resistant depression (TRD).  Given our preliminary data, we hypothesise that PAR2 activation induces depression-like behaviour via inflammatory mechanisms.  Thus the aim of this project is test the this hypothesis by examining the following research questions:

 

  1. What inflammatory cell types are involved in PAR2-induced depression-like behaviour?
  2. What cellular and signalling pathway(s) underlie PAR2-induced behavioural changes?
  3. Does peripheral inflammation plays a role in the centrally-mediated behavioural changes?

 

Answer to these questions will identify a potential novel therapeutic target for those patients who are resistant to current therapies for MDD.

 

Techniques used:

 

Behavioural testing of depression-like behaviour, immunohistochemistry, innate and adaptive immune cell assays using FACS analysis, cytokine assays using ELISA.

Funding Details

Running costs of £10000 p.a. will be associated with this project in addition to University tuition fees.

Further information

1: Bushell TJ, Cunningham MR, McIntosh KA, Moudio S, Plevin R. Protease-Activated Receptor 2: Are Common Functions in Glial and Immune Cells Linked to Inflammation-Related CNS Disorders? Curr Drug Targets. 2016;17(16):1861-1870.

2: Gan J, Greenwood SM, Cobb SR, Bushell TJ. Indirect modulation of neuronal excitability and synaptic transmission in the hippocampus by activation of proteinase-activated receptor-2. Br J Pharmacol. 2011 163:984-94.

3: Greenwood SM, Bushell TJ. Astrocytic activation and an inhibition of MAP kinases are required for proteinase-activated receptor-2-mediated protection from neurotoxicity. J Neurochem. 2010 113:1471-80.

4: Abulkassim R, Brett R, MacKenzie SM, Bushell TJ. Proteinase-activated receptor 2 is involved in the behavioural changes associated with sickness behaviour. J Neuroimmunol. 2016 295-296:139-47.