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乳头中神经节细胞轴突的直接细胞环境。它们占据该位置处的总组织体积的高达50%。当视网膜神经节细胞的轴突受损时，它们会变得“反应性”。“在拟议的研究中，我们研究了触发这种反应的视神经轴突和星形胶质细胞之间的信号传导。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间。我们的初步结果表明，非常不同的神经胶质细胞基因组上调或下调在不同的时间轴突损伤后。具体目标1的实验试图证实这一发现，使用改进的轴突损伤模型。具体目标2使用我们现有的和未来的表达谱的结果，以确定候选人的信号系统，从轴突到星形胶质细胞通信。使用病毒载体，候选信号将在视网膜神经节细胞中过表达。预测是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。 具体目标3研究了星形胶质细胞的初始反应 对轴突损伤的保护作用是保护性的，即受到损伤威胁的视网膜神经节细胞向成鞘星形胶质细胞发送求救信号，然后星形胶质细胞启动神经保护反应。我们将测试这一假设，强调在转基因小鼠的视神经携带突变，损害星形胶质细胞的沟通和运动。预测是星形胶质细胞功能的损害将加重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.