My research focuses on inflammation in disease. During my PhD I studied how the activation of an immune response in the absence of infection, a phenomenon known as ‘sterile inflammation’, can be damaging in brain disease such as Alzheimer’s disease and how this can be driven by pro-inflammatory cytokines of the interleukin-1 family. Now, working for the UK Dementia Research Institute in Edinburgh, I’m studying how microglial cells are involved in driving damage or resilience in neurodegenerative diseases such as Alzheimer’s disease and vascular dementia.
Microglia in neurodegenerative disease
Microglial cells are the primary immune cells of the brain. After years of believing dementias to be independent of inflammation and immune activation we now understand that microglia play a key role in regulating the pathogenesis and progression of numerous neurodegenerative diseases. However, we do not currently understand how these cells seem to be both damaging in some situations but protective in others. I’m particularly interested in how regulators of lysosomal function (subcellular structures that carry out protein degradation) in microglia are involved in neurodegenerative disease.
Inhibiting the NLRP3 inflammasome in brain disease
The most extensively studied of the interleukin-1-family cytokines is IL-1β. Unlike most proteins, which are secreted from the cell via the endoplasmic reticulum and Golgi body, IL-1β is secreted via unconventional mechanisms that are dependent on a large multimolecular complex called an inflammasome. Activation of inflammasome has been implicated in the pathology of a whole host of diseases including stroke, diabetes, atherosclerosis, Alzheimer’s disease, and many others. However, there are currently no clinical available inhibitors of the inflammasome.
Therefore, there is a huge clinical unmet need for inflammasome-inhibiting drugs to treat diseases such as those above. I have previoulsy worked both on designing new drugs (to allow for potent and specific inhibition of the inflammasome) and repurposing currently available drugs (to allow for rapid introduction of safe and effective inflammasome inhibiting drugs) with the aim of making a step-change in the treatment of diseases such as Alzheimer’s and stroke.
Investigating the regulation of IL-1α
The mechanisms underlying IL-1β-signalling are relatively well known. However, the regulation of the closely related IL-1α is poorly understood. Whereas IL-1β is secretion is dependent on the inflammasome, IL-1α may be regulated by other mechanisms such as post-translational processing and its subcellular localisation. Like IL-1β, IL-1α is implicated in numerous diseases such as stroke, atherosclerosis and cancer and there is interest in using drugs to block IL-1α signalling to treat these diseases. But we still understand very little about the physiological regulation of IL-1α.
I have previoulsy worked to understand how IL-1α is regulated by using genetic techniques to prevent its translocation to the nucleus and by using drugs to inhibit the enzymes involved in its post-translational processing. We hope that this research will improve the understanding of IL-1α and therefore may aid in the development of drugs attempting to modulate IL-1α signalling to treat disease such as stroke.