The Induction of Reactivity in Optic Nerve Astrocytes

描述(申请人提供)：在人类和小鼠中，星形胶质细胞形成视神经头中神经节细胞轴突的直接细胞环境。它们占据了该部位组织总体积的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”。在这项拟议的研究中，我们研究了视轴突和星形胶质细胞之间触发这种反应的信号。第一个问题是视神经轴突受损后基因表达变化的性质和时机。我们的初步结果表明，在轴突损伤后的不同时间，非常不同的神经胶质基因集被上调或下调。《特定目标1》的实验试图利用改进的轴突损伤模型来证实这一发现。特定目标2使用我们现有和未来表达谱的结果来确定从轴突到星形胶质细胞的信号系统的候选。候选信号将通过病毒载体在视网膜神经节细胞中过度表达。预测是，一个实际信号的过度表达将导致星形胶质细胞基因表达和星形胶质细胞反应性的形态特征的变化。特指目标3研究了星形胶质细胞的初始反应 对轴突的损伤是一种保护性损伤，即视网膜神经节细胞受到损伤威胁时向包被的星形胶质细胞发出求救信号，然后星形胶质细胞启动神经保护反应。我们将通过对携带损害星形胶质细胞通讯和运动性突变的转基因小鼠的视神经施加压力来检验这一假设。据预测，星形胶质细胞功能的损害将加剧这种压力对轴突的损害。

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.