The Induction of Reactivity in Optic Nerve Astrocytes

描述（由申请人提供）：在人和小鼠中，星形胶质细胞形成视神经头神经节细胞轴突的直接细胞环境。它们占据了该部位总组织体积的50%。当视网膜神经节细胞的轴突受损时，它们就会变得“反应性”。在这项研究中，我们研究了视轴突和星形胶质细胞之间的信号传导，触发了这种反应。第一个问题是视觉轴突损伤后基因表达变化的性质和时间。我们的初步结果表明，不同的神经胶质基因在轴突损伤后的不同时间被上调或下调。Specific Aim 1的实验试图用一种改进的轴突损伤模型来证实这一发现。特异性目标2使用我们现有的和未来的表达谱分析的结果来确定从轴突到星形胶质细胞通信的信号系统的候选者。候选信号将被过度表达，使用病毒载体，在视网膜神经节细胞。预测某一实际信号的过表达会导致星形胶质细胞基因表达和星形胶质细胞反应性形态特征的改变。特异性目的3探讨星形胶质细胞的初始反应假说

DESCRIPTION (provided by applicant): In both humans and mice, astrocytes form the immediate cellular environment of the ganglion cell axons in the optic nerve head. They occupy up to 50% of the total tissue volume at that location. When the axons of retinal ganglion cells are damaged, they become "reactive." In the proposed research we investigate the signaling between optic axons and the astrocyte that triggers this response. The first question is the nature and timing of the changes in gene expression that follow damage to the optic axons. Our preliminary results indicate that very different sets of glial genes are up or down regulated at different times following axonal injury. The experiments of Specific Aim 1 seek to confirm this finding, using an improved model of axonal damage. Specific Aim 2 uses the results of our existing and future expression profiling to identify candidates for the signaling systems that communicate from axons to astrocytes. The candidate signals will be overexpressed, using viral vectors, in retinal ganglion cells. The prediction is that overexpression of an actual signal will lead to the changes in astrocyte gene expression and morphology characteristic of astrocyte reactivity. Specific Aim 3 investigates the hypothesis that the initial response of the astrocytes to axonal damage is a protective one, i.e. that retinal ganglion cells threatened with injury send a distress signal to the ensheathing astrocytes, which then initiate a neuroprotective response. We will test this hypothesis by stressing the optic nerve in transgenic mice carrying mutations that compromise astrocyte communication and motility. The prediction is that the compromise of astrocyte function will worsen the damage to the axons resulting from this stress.