Cell Signalling Laboratory

Professor Jennifer Pocock

Microglia, the immune cells of the brain, are implicated in signalling cascades leading to neuronal death in an increasing number of neurodegenerative diseases, including Alzheimer's disease, multiple sclerosis, Parkinson's disease and also in acute conditions such as those following stroke. Using cell-based systems, currently human iPSC-derived cells, we are investigating signalling cascades which occur in microglia following their exposure to substances implicated in their activation in particular neurodegenerative diseases. Our aim is to dissect out the pathways of neuronal and astrocyte dysfunction which may result from microglial activation.

Our research focus currently is modelling neurodegenerative processes using human iPSC derived microglia, astrocytes and neurons. Current projects involve investigating how TREM2, CD33 and other genetic risk variants linked to neurodegeneration influence microglial behaviour and the knock-on effects of these variants on neurons and astrocytes. We are interested in the metabolic effects of these variants on microglia and have shown that microglia expressing the AD risk variant R47H display an inability to undergo a metabolic switch from oxidative phosphorylation to glycolysis when activated. This has ramifications for their responses in the human brain. Another project involves how microglial exosomes, the most prevalent form of extracellular vesicle (EV) shed from microglia, differ in their size, quantity and content in TREM2 AD-linked variants compared with common variant microglia. Furthermore, our research has investigated how these different microglial derived exosomes impact on neuronal survival, stress responses and gene expression. We are also interested in the impact on microglia and other brain cells of blood-derived proteins such as fibrinogen and albumen, which are normally excluded from the brain, but which enter the brain when the blood brain barrier becomes damaged.

A long-standing interest is in the role of microglial expressed neurotransmitter receptors, particularly metabotropic glutamate receptors and how these control the microglial responses. We also have a number of projects collaborating with drug companies to set up assays for drug screening. These include phagocytosis, cell survival, migration, phosphorylation and kinase assays, receptor ligand interactions, cytokine/chemokine/stress array proteome analyses, Seahorse metabolic assays and Opera Phenix High content screening platforms.