Investigating cellular metabolism and inter-organelle dynamics in glial cells
Summary
Microglia, the resident immune cells of the central nervous system (CNS), exhibit remarkable functional diversity, shifting between states to respond to their environment. In disease, microglia often adopt a persistent activation state that drives chronic neuroinflammation and subsequent neural damage.
In progressive multiple sclerosis (P-MS), this harmful phenotype is linked to dysfunctional mitochondria, which lead to the sustained production of mitochondrial reactive oxygen species (mtROS). However, the precise molecular triggers that alter microglial mitochondrial metabolism in P-MS remain poorly understood.
Recent work from our lab has shown that bioactive metabolites found within demyelinating lesions in post-mortem P-MS brain tissue can alter microglial metabolism, as well as the morphology and function of microglial organelles. The communication between these organelles often occurs at specialized membrane contact sites (MCSs), which are critical for the exchange of ions, metabolites, and radicals.
Despite emerging evidence, the role of dysfunctional organelle crosstalk in shaping microglial states during chronic inflammation is largely unexplored. This project will investigate the link between cellular metabolism, inter-organelle dynamics, and glial cell function in the context of chronic inflammation.
Project aims
- To characterise the metabolic, functional and structural changes in inter-organelle dynamics that occur in microglia when challenged with relevant stimuli identified in the P-MS tissue microenvironment.
- To investigate how alterations at membrane contact sites (MCSs) impact organelle crosstalk and overall microglial function.
- To determine whether therapeutically restoring normal function at MCSs can reinstate healthy microglial effector functions and promote neuronal health.
This project will use a combination of in vitro and ex vivo approaches to investigate how organelle interactions are altered in the context of persistent brain inflammation. The primary cellular models will be human induced pluripotent stem cell-derived microglia (hiMG) and hiMG-neuron co-culture systems.
To simulate chronic inflammatory conditions, these cultures will be challenged with specific bioactive metabolites that our lab previously identified within the tissue microenvironment of P-MS lesions. This experimental approach is crucial because it allows us to recreate and study the persistent microglial activation that drives chronic neuroinflammation and neural damage in P-MS.
We will employ advanced microscopy techniques to visualize structural changes at an ultrastructural level, alongside molecular techniques and genetic manipulations to probe function. Key findings will be validated in human post-mortem brain samples from P-MS patients.
By integrating data from advanced cellular models and human tissue, this project will reveal how inter-organelle communication in microglia is altered in chronic neuroinflammatory diseases like P-MS.
This research aims to identify novel metabolic and molecular targets involved in regulating organelle contacts, potentially opening new therapeutic avenues to modulate microglial function and mitigate neurodegeneration.
Contact details
Dr Luca Peruzzotti Jametti (lp429@cam.ac.uk) – Neurology
Opportunities
This project is open to applicants who want to do a:
- PhD
- MPhil