Understanding how the P2X7 NLRP3 signalling axis contributes to the aetiology of neuropsychiatric disease

Neuroinflammation is increasingly recognized to play a role in a number of neuropsychiatric diseases including Alzheimer’s disease, depression and schizophrenia. Microglia are primarily responsible for activation of the immune system response in the brain. The NLRP3 inflammasome is an extensively studied protein complex responsible for the formation of pro-inflammatory cytokines, interleukin (IL)-1beta and IL-18.

This project will study the contribution of the P2X7 receptor – NLRP3 signalling axis to microglia function and dysfunction in neuroinflammation. Genetic models have demonstrated the role of NLRP3 in the pathology of Alzheimer’s disease, the formation of amyloid-beta plaques and the M1 polarization of microglia (Heneka et al, 2013). Cerebrovascular abnormalities are associated with the severity of AD symptoms and neurodegeneration (Neilsen et al, 2017). We have demonstrated oxygen sensitivity of the NLRP3 inflammasome pathway in brain microglia (Wickens et al, 2015). The student will study the pathways responsible for oxygen sensitivity of P2X7 receptor-NLRP3 inflammasome signalling in microglia.

Based in the Department of Pharmacy & Pharmacology within the Drug & Target Discovery research theme which provides a multidisciplinary interactive research environment. The project provides an excellent opportunity for training in molecular, electrophysiological and cell biology methods. The University hosts a Microscopy and Analysis Suite with specialist training in multiphoton imaging, hypoxic plate readers and flow cytometry (http://www.bath.ac.uk/facilities/mas).

Research training will include cell culture, the use of the hypoxic facilities, single cell electrophysiology, fluorescent imaging and near-infrared fluorescent western blot.