Understanding and targeting inflammation in brain disease

Inflammation is an established contributor to the worsening of brain injury and disease, such as Alzheimer's disease. In many cases of neurodegenerative disease inflammation arises as a result of the formation of a multi-molecular pro-inflammatory complex called the NLRP3 inflammasome. The signals, mechanisms, and sub-cellular compartments that coordinate activation of the NLRP3 inflammasome remain unknown. However, our preliminary evidence suggests that specific stress of sub-cellular organelles serves as an activation signal. Using state-of-the-art cell and molecular biology combined with high resolution imaging, the aim of this project is to interrogate the mechanisms of NLRP3 inflammasome activation in response to diverse cellular stresses. Once characterised the 'fingerprint' of cellular activation will be investigated in disease brain tissue from the Manchester Brain Bank. Disease relevant mechanisms will then be targeted in experimental models to provide a new proof of concept against the inflammatory pathways uncovered. Overall, this project will lead to new understanding of inflammatory mechanisms in the brain, how they contribute to disease, and an understanding of how they can be targeted therapeutically