Studies in Glaucomatous Optic Nerve Damage

项目摘要 了解眼内压（IOP）诱导的轴突损伤的细胞机制将有助于开发新的 保护视神经的青光眼治疗。我们的眼压控制性升高（CEI）模型产生光学 神经头（ONH）基因表达的变化和视神经（ON）的损害，平行于那些观察到的， 慢性模型。RNAseq时程分析显示，IOP产生几种细胞因子的早期激活。 主要途径及其组分的具体回收。我们现在已经开发出一种方法 清醒大鼠的清醒CEI（aCEI）暴露，使用外部留置的前房插管， 容易接近这将使我们能够研究慢性青光眼的事件，这些事件发生在相对较短的时间内， 实验室设置的短时间框架。 在具体目标1中，我们将（a）证明在40 mmHg下8小时aCEI几乎不会产生损伤 与50 mmHg相比，（B）显示非损伤性的较低IOP将产生ONH基因表达变化 其小于但在性质上类似于在损伤性较高IOP下所见的那些，并且（c）表明， 在老年动物中暴露于aCEI将比成年动物中相同水平的压力产生更大的损伤 动物 具体目标2将表明，（a）在初始的类似暴露之后， 将影响轴突损伤的累加性，以及（B）重复的时间，损伤性aCEI将影响ONH基因 表达和恢复。 具体目标3将证明（a）重复aCEI可用于模拟“慢性”视神经胶质瘤 神经损伤，（B）具有压力诱导的视神经损伤的眼睛将更容易受到随后的IOP的影响 （c）IOP波动比相同水平的暴露产生更多的伤害， IOP在相同的持续时间内保持稳定状态。 这些在未麻醉动物中进行的研究使用的IOP水平，相对于正常的平均大鼠IOP， 与人类青光眼相当，并且将提供人类青光眼的这方面的最准确的表示。 实验室老鼠可能患上的疾病他们将提供独特的见解细胞机制的慢性 青光眼视神经损伤，并允许研究以前无法接近的方面，这一慢性 疾病

Project Summary Understanding cellular mechanisms of intraocular pressure (IOP)-induced axonal injury will help develop new glaucoma treatments that protect the optic nerve. Our Controlled Elevation of IOP (CEI) model produces optic nerve head (ONH) gene expression changes and optic nerve (ON) damage that parallel those observed in chronic models. An RNAseq time-course analysis has revealed that IOP produces early activation of several major pathways and specific recovery of their components. We have now developed a method of creating awake CEI (aCEI) exposures in conscious rats using an indwelling anterior chamber cannula that is externally accessible. This will allow us to study events of chronic glaucoma, which occurs over years, in the relatively short time frame of a laboratory setting. In Specific Aim 1, we will (a) demonstrate that an 8-hour aCEI at 40 mmHg will produce little to no injury compared to 50 mmHg, (b) show that a non-injurious, lower IOP will produce ONH gene expression changes that are less than, but qualitatively similar, to those seen with an injurious, higher IOP and (c) show that exposure to aCEI in elderly animals will produce greater injury than the same level of pressure in adult animals. Specific Aim 2 will show that (a) the timing of a second, injurious aCEI following an initial, similar exposure will affect additivity of the axonal injury and (b) the timing of a repeat, injurious aCEI will affect ONH gene expression and recovery. Specific Aim 3 will demonstrate that (a) repeat aCEI can be used to model “chronic” glaucomatous optic nerve damage, (b) an eye with pressure-induced optic nerve injury will be more susceptible to subsequent IOP exposure than an eye without prior injury and (c) IOP fluctuations produce more injury than the same level of IOP maintained at a steady state for the same duration. These studies in unanesthetized animals use levels of IOP that, relative to normal, mean rat IOP, are comparable to human glaucoma, and will provide the most accurate representation of this aspect of the human disease possible in laboratory rats. They will provide unique insights into cellular mechanisms of chronic glaucomatous optic nerve damage and allow study of previously unapproachable aspects of this chronic disease.