调控视神经星形胶质细胞STAT3信号传导通路对视神经的保护作用

Vision loss in glaucoma is caused by the dysfunction and death of retinal ganglion cells (RGCs).The initial insult to the axons of RGCs is in an astrocyte-rich region of the optic nerve, called lamina cribrosa. Intraoccular pressure elevation in some way activates these astrocytes so that they damage the RGC axons. The mechanisms of the astrocytes activation in optic nerve are not well understood. In the previous studies, we found that STAT3 signaling pathway is important in the activation of astrocytes in optic nerve. In this study, we will use Thy1-CFP DBA/2J mouse model to investigate the relationship between optic nerve astrocytes activation and RGCs survival.Thy1-CFP DBA/2J has a prodominant DBA/2J genetic background, CFP-expressing RGCs, and age related progressive glaucoma. We detect the activation of astrocytes between glaucomatous mice and the normal intraoccular pressure mice. The STAT3 signaling pathway of the astrocytes is identified in different stage of the glaucoma mice. We will use different inhibitor of STAT3 to inhibit the activation of the astrocytes and observe the RGCs survival in different conditions. However, the critical gene targets of STAT3 that mediate astrocytes activation have remained unknown. CyclinD1、BAX、Bcl2、Caspase-9、NFκB，iNOS were reported to be the downstream target gene of STAT3 in many other celllines. In this study, we will testify the above genes in astrocytes. Furthermore, we will try to find new critical downstream target of STAT3 in astrocyte activation. Knockdown the specific downstream gene will be performed to identify the function of the STAT3 downstream gene on astrocytes activation and ganglion cell survival. These experiments will offer evidences for the association between astrocytes activation and RGCs' survival. Our findings provide mechanistic insight into how STAT3 stimulates astrocytes. The finding of the novel gene target of STAT3 in astrocytes may have potential therapeutic value in neuroprotection.

本项目拟研究抑制视神经星形胶质细胞活化对视网膜神经节细胞的保护作用。已知视神经乳头的星形胶质细胞在青光眼视神经病变过程中由静止状态转变为活化状态，对视神经节细胞轴索产生多种有害影响。我们前期实验已证实急性眼压升高的模型中，视神经星形胶质细胞激活的程度与视神经的损伤平行，并观察到STAT3介导了该细胞的活化。本研究拟应用慢性青光眼动物模型Thy1-CFP-DBA/2J小鼠，观察星形胶质细胞在青光眼发生过程中的激活特点、视神经周围微环境的改变以及激活的信号传导通路。并进一步应用多种途径阻断STAT3信号传导通路，探究抑制星形胶质细胞激活对视神经的保护作用。并通过多种技术探究STAT3的下游基因如CyclinD1、BAX、Bcl2、Caspase-9、NFκB，iNOS在该细胞活化中的作用，寻找与胶质细胞激活相关的STAT3下游基因，为进一步抑制星形胶质细胞的活化提供可能的靶点。

本项目拟研究抑制视神经星形胶质细胞活化对视网膜神经节细胞的保护作用。已知视神经乳头的星形胶质细胞在青光眼视神经病变过程中由静止状态转变为活化状态，对视神经节细胞轴索产生多种有害影响。我们前期实验已证实急性眼压升高的模型中，视神经星形胶质细胞激活的程度与视神经的损伤平行，并观察到STAT3介导了该细胞的活化。本研究拟应用慢性青光眼动物模型Thy1-CFP-DBA/2J小鼠，观察星形胶质细胞在青光眼发生过程中的激活特点、视神经周围微环境的改变以及激活的信号传导通路。并进一步应用多种途径阻断STAT3信号传导通路，探究抑制星形胶质细胞激活对视神经的保护作用。并通过多种技术探究STAT3的下游基因如CyclinD1、BAX、Bcl2、Caspase-9、NFκB，iNOS在该细胞活化中的作用，寻找与胶质细胞激活相关的STAT3下游基因，为进一步抑制星形胶质细胞的活化提供可能的靶点。