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


Project Description

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.

Funding Notes

Applications are welcome year-round from Home/EU/Overseas self-funded students and applicants able to secure funding to cover all costs involved with PhD study, including living costs, tuition fees and bench fees.

References

Heneka et al 2013 NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature. 493(7434) 674- 8
Neilsen R.B. et al. 2017 Capillary dysfunction is associated with symptom severity and neurodegeneration in Alzheimer’s disease. Alzheimers Dement. Doi. 10.1016/j.jalz.2017.02.007
Wickens, R., Ver Donck, L., Bailey, S. and Mackenzie, A., 2015. Primary microglia isolated from neonatal mice provide a model for the study of NLRP3 inflammasome and the effect of long-term hypoxia. In: Society for Neuroscience 2015, 2015-10-17 - 2015-10-21, Chicago.

How good is research at University of Bath in Allied Health Professions, Dentistry, Nursing and Pharmacy?

FTE Category A staff submitted: 54.20

Research output data provided by the Research Excellence Framework (REF)

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