Understanding the mechanisms that drive NLRP3-dependent inflammation

Acute cerebrovascular disease remains a major area of unmet clinical need and can present as a range of clinical conditions, from periventricular haemorrhage in preterm babies, through subarachnoid haemorrhage (SAH), ischaemic and haemorrhagic stroke (1). Cerebral cavernous malformations (CCMs) are common vascular malformations occurring within the brain that predispose the affected individual to an increased risk of haemorrhage. It was recently reported that the formation of CCMs in a rodent model was dependent upon TLR4-driven inflammation (2). The NLRP3 inflammasome is a multi-molecular complex that drives inflammation and is an emerging therapeutic target for many major diseases including brain haemorrhage. The NLRP3 inflammasome also requires a TLR4-dependent priming step. In this project we will seek to understand the mechanisms regulating the NLRP3 inflammasome. We have developed a unique suite of tools and reagents for interrogating NLRP3 dependent responses and this represents an outstanding opportunity to identify new therapeutic targets and strategies for diseases with a massive unmet clinical need.