The NLRP3 inflammasome: a prospective therapeutic target for intracerebral haemorrhage

脑出血（ICH）后，有毒血液流入大脑引发促炎反应，推动脑损伤的进展，并代表一个潜在的治疗靶点。迄今为止，还没有针对脑出血患者的特异性药物治疗方法。因此，迫切需要确定新的候选疗法。炎性小体，如由NLRP3形成的，是炎症细胞对致病性感染和组织损伤反应形成的胞质多聚体蛋白复合物。激活的炎性小体驱动促炎细胞因子前体如il - 1b和il -18转化为成熟的分泌形式，从而引发炎症。事实上，炎性体激活在脑出血后的脑损伤中起着关键作用，选择性NLRP3抑制可能对啮齿动物模型有保护作用。通过斑马鱼药物筛选，我们发现了一系列可以抑制ICH后脑损伤的小分子化合物（PMID: 35098999）。我们假设其中一些分子通过抑制NLRP3炎性体提供保护。在本博士课程中，我们将通过在体外炎症小体激活模型中进一步筛选这些成功的化合物来测试这一假设的有效性。能够抑制NLRP3炎性体的候选药物随后将在两个独立的体内ICH模型系统（斑马鱼和小鼠）中进行测试和询问，以确定对疾病结局的影响。因此，学生将获得跨学科转化研究（药物化学，免疫学，神经科学）的培训，并获得与细胞分析和斑马鱼/小鼠疾病建模相关的技能。该学生将加入更广泛的脑炎小组，这是一个充满活力和成功的小组，由非临床和临床PI，博士后，学生和技术人员组成，他们的研究范围从基础生物学到临床实践。这种多样化的研究环境为工作和培训提供了一个刺激和有趣的地方。

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.