GLAUCOMATOUS OPTIC NERVE DAMAGE

了解眼内压（IOP）升高如何损害视神经 纤维将导致新的青光眼治疗专门指定， 保护视神经纤维。为了长期研究这种关系 在大鼠中已经产生了升高的IOP;导致进行性的、区域性的 神经节细胞轴突变性，视神经头杯状， 细胞外基质成分与筛板的沉积-所有 人类疾病的特征。定量超微结构 对这些视神经横截面的分析表明， 轴突失去了正常的圆形轮廓轴突形状的丧失 在轻度IOP升高的眼睛中观察到的萎缩， 压力更高，并且在区域和神经中更明显， 更大的轴突变性。 压力引起的视神经损伤的萎缩现象表明 一个新的假设：眼压升高通过产生一个 进行性轴突萎缩，最终导致变性。 了解这种萎缩的性质及其与 变性将是了解青光眼机制的关键 视神经损伤本提案将开始确定IOP如何产生 轴突萎缩，显示它是区域性相关的轴突 在一定范围内的IOPS退化。形态分析将确定 这种萎缩是否是由于神经丝数量减少和/或 微管改变其排列，或两者兼而有之。解释 这些发现将得到动态测量细胞骨架mRNA的帮助。 以及蛋白质的产生和缓慢的轴突运输，这两者都会影响 轴突体积使用这种多方面的实验方法， 该提案将确定哪些主要过程控制轴突的大小 受IOP的影响，并导致更具体的假设， 青光眼中压力诱导萎缩和轴突变性的机制。

Understanding how elevated intraocular pressure (IOP) damages optic nerve fibers will lead to new glaucoma therapies designated specifically to protect optic nerve fibers. To study this relationship, chronically elevated IOP has been produced in rats; resulting in progressive, regional degeneration of ganglion cell axons, optic never head cupping, and deposition of extracellular matrix components with the lamina cribrosa-all characteristics of the human disease. Quantitative ultrastructural analysis of cross sections from these optic nerves show that the remaining axons lose their normal, round profiles. This loss of axonal shape (atrophy), observed in eyes with mild IOP elevation, develops more rapidly with higher pressure, and is more pronounced in regions and nerves with greater axonal degeneration. The appearance of atrophy in pressure-induced optic nerve damage suggests a new hypothesis: elevated IOP damages optic nerves by creating a progressive axonal atrophy that leads eventually to degeneration. Understanding the nature of this atrophy and its relationship to degeneration will be key to understanding the mechanism of glaucomas optics nerve damage. This proposal will begin determining how IOP produces axonal atrophy by showing that it is regionally associated with axonal degeneration over a range of IOPs. Morphometric analysis will determine whether this atrophy is due to diminished numbers of neurofilaments and/or microtubules to alterations in their arrangement, or both. Interpreting these findings will be aided by dynamic measurements of cytoskeletal mRNA and protein production and slow axonal transport, both of which affect axonal volume. Using this multifaceted experimental approach, this proposal will determine which of the major processes governing axon size are affected by IOP, and lead to more specific hypothesis concerning the mechanism of pressure-induced atrophy and axonal degeneration in glaucoma.