AcCystatin/小胶质细胞/TNF-α轴介导广州管圆线虫感染所致小鼠神经元坏死性凋亡的机制研究

尽管广州管圆线虫是嗜酸性粒细胞增多性脑膜脑炎的最常见感染性因素，但感染者中枢神经系统（CNS）功能严重受损的分子机制仍是广州管圆线虫病防治研究亟需回答的关键科学问题。我们率先发现：广州管圆线虫感染可致小鼠CNS出现明显坏死性凋亡，且神经元为坏死性凋亡的主要细胞类群，其发生机理与虫源性免疫调节分子AcCystatin及其上调小胶质细胞TNF-ɑ密切相关。本项目拟进一步采用基因敲除虫体、RNAi、免疫共沉淀、Confocal、透射电镜术、芯片检测等技术系统研究广州管圆线虫感染所致小鼠神经元坏死性凋亡的分子机制，为确定以AcCystatin、TNF-ɑ或活化小胶质细胞为治疗靶标的广州管圆线虫病新治疗策略提供科学依据。

Angiostrongylus cantonensis (A. cantonensis), the rat lungworm, is the most common infectious cause of eosinophilic meningoencephalitis worldwide, however, the pathogenensis of severe damages to the central nerve system (CNS) of the patients cause by the parasite remains unclear. The observation in our study firstly demonstrated that striking necroptosis was detected in the CNS, especially in neurons, of infected mice, and AcCystatin, an immunoregulatary molecule from A. cantonensis and high level TNF-ɑ released by AcCystatin-pretreated microglia might be the key causes of neuron necroptosis..Based on our previous findings, the biotechnics such as Knock out parasites, RNAi, knock-out mice, microarray chip, Co-Immunoprecipitation, Confocal microscopy, transmission electron microscopy, et al. were proposed to investigate the molecular mechanism of necroptosis in neurons of mice after the infection. Our proposed study will contribute greatly to the development of a novel strategy to reduce the neurological damages caused by this parasite.