The NLRP3 inflammasome: a prospective therapeutic target for intracerebral haemorrhage

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Following intracerebral haemorrhage (ICH), the toxic influx of blood into the brain initiates a pro-inflammatory response that drives the progression of brain injury and represents a potential therapeutic target. To-date, no specific drug treatments exist for ICH patients. As such, there is an urgent requirement to identify new candidate therapies.Inflammasomes, such as formed by NLRP3, are cytosolic multimeric protein complexes formed in inflammatory cells in response to pathogenic infection and tissue injury. Activated inflammasomes drive the processing of pro-inflammatory cytokine precursors such as pro-IL-1B and pro-IL-18 into mature secreted forms to initiate inflammation. Indeed, inflammasome activation plays a key role in driving brain injury following ICH and selective NLRP3 inhibition may be protective in rodent models.Through zebrafish drug screening, we have identified a series of small molecule compounds that can inhibit brain injury after ICH (PMID: 35098999). We hypothesise that some of these molecules offer protection through inhibiting the NLRP3 inflammasome. In this PhD, we will test this hypothesis by further screening these successful compounds in an in vitro model of inflammasome activation to test for efficacy. Candidates capable of inhibiting the NLRP3 inflammasome will be subsequently tested and interrogated in two separate in vivo ICH model systems (zebrafish and mouse) to determine effects on disease outcomes. As such, the student will gain training in cross-disciplinary translational research (medicinal chemistry, immunology, neuroscience), and acquire skills associated with cellular assays and zebrafish/mouse disease modelling.The student will join the wider Brain Inflammation group, a vibrant and successful group of non-clinical and clinical PI's, post-docs, students and technicians whose research spans from basic biology through to clinical practise. This diverse research environment provides a stimulating and fun place to work and train.