Metabolic Determinants of Astrocyte – Microglial Interactions in Smoldering Brain Disease
Summary
Progressive multiple sclerosis (PMS) is characterised by a persistent state of inflammation that is mediated, in part, by microglia. Activated microglia communicate with astrocytes in the local microenvironment to perpetuate this inflammation.
Recent work suggests that end-products of cell metabolism (metabolites) can guide the activation of microglia and their communication with the microenvironment.
Among tricarboxylic acid cycle metabolites, succinate plays a key signalling role in conditions of persistent neuroinflammation.
Intracellular succinate guides pro-inflammatory microglia effector functions whereas extracellular succinate released by microglia signals to surrounding cells through its metabolic sensor succinate receptor 1 (SUCNR1).
We hypothesise this establishes a feedback loop that regulates the dynamics of the acquisition of pro- and anti-inflammatory features by microglia and astrocytes, respectively.
Project aims
This project will first investigate the role and function of SUCNR1 in directing the response of human microglia in pro-inflammatory conditions in vitro using a state-of-the-art gene editing technique to modify the expression of SUCNR1 on human microglia.
From this, the succinate-SUCNR1 signalling axis between human microglia and astrocytes will be explored using a sophisticated co-culture system.
Combining human disease modelling in a dish with advanced molecular biology and imaging techniques, this project aims to provide new molecular insights into the function of SUCNR1 on human microglia in inflammatory conditions.
This will uncover new signaling functions of immunometabolites in chronic neuroinflammation, unveil novel mechanisms of neuroimmune interactions, and be instrumental in discovering new and relevant therapeutic targets to help stop the accumulation of irreversible disabilities in PMS patients.
Contact details
Professor Stefano Pluchino - spp24@cam.ac.uk
Opportunities
This project is open to applicants who want to do a:
- PhD
- MPhil