Caspase-8-NLRP1/3信号通路在BMMSCs保护青光眼视神经损伤的作用

项目名称： Caspase-8-NLRP1/3信号通路在BMMSCs保护青光眼视神经损伤的作用

项目编号： No.81470627

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 卓业鸿

作者单位： 中山大学

项目金额： 73万元

中文摘要： 免疫炎症机制是青光眼视神经继发性损伤的重要机制之一，而小胶质细胞是神经继发性损伤的核心。我们前期研究发现TLR4在小鼠急性高眼压模型中发挥关键损伤作用，并诱导小胶质细胞中caspase-8信号活化，介导视网膜神经节细胞（RGCs）损伤。为深入探讨caspase-8如何激活相关下游信号介导RGCs损伤，本研究拟在急、慢性高眼压小鼠模型和骨髓间充质干细胞（BMMSCs）与小胶质细胞共培养模型的基础上，围绕caspase-8-NLRP1/3通路，研究小胶质细胞活化和炎症小体激活介导的RGCs损伤分子机制。同时，探讨BMMSCs如何通过其抗炎和免疫调节的生物学特性参与RGCs损伤保护。从基因、分子和细胞水平，探讨caspase-8-NLRP1/3通路在青光眼视神经损伤发病机制，BMMSCs移植治疗RGCs损伤中的作用，为青光眼治疗寻找新的靶点，为BMMSCs治疗青光眼的临床转化奠定理论基础。

中文关键词： 视网膜神经节细胞；骨髓间充质干细胞；小胶质细胞；caspase-8信号通路；炎症小体

英文摘要： Immunoinflammation is a vital mechanism of secondary retinal ganglion cells (RGCs) damage in glaucoma, and microglia also plays pivotal role in secondary CNS injury. Recently, we have found that Toll-like receptor 4 (TLR4), which caused RGCs damage via cysteinyl aspartate specific proteinase-8 (caspase-8) activation, plays a key role in acute ocular hypertension mice model.However,the relevant downstream is not clear. To explore how caspase-8 activates its associated downstream pathways and medicates RGCs damage, this study focuses on caspase8-NLRP1/3 pathway in order to clarify the molecular mechanism of microglia and inflammasome activation induced RGCs damage on the basis of the acute, chronic ocular hypertensive mice models and bone marrow mesenchymal stem cells (BMMSCs)/microglia co-culture models. Meanwhile, this study also aims to explore how BMMSCs protect RGCs damage via their anti-inflammatory and immunomodulatory characteristics. Finally, from genic, molecular and cellular levels, we hope to explore the mechanism of how caspase-8-NLRP1/3 pathway mediates glaucomatous RGCs damage and the neuroprotective effects of BMMSCs , so as to find a new target for the treatment of glaucoma and lay the theoretical foundations for the clinical transformation of BMMSCs transplant therapy in glaucoma.

英文关键词： retinal ganglion cells;bone marrow mesenchymal stem cells;microglia;caspase-8 pathway;inflammasome