Studies in Glaucomatous Optic Nerve Damage

项目摘要 了解眼压引起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。我们的可控眼压升高(CEI)模型产生光学 神经头(ONH)基因表达的变化和视神经(ON)损害与观察到的相似 慢性病模特。RNAseq的时程分析表明，IOP会产生几种早期激活 主要途径及其成分的具体回收。我们现在已经开发出一种方法来创建 清醒大鼠应用外置前房导管进行清醒CEI暴露的实验研究 无障碍。这将使我们能够研究慢性青光眼的事件，这种事件发生多年，在相对 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毫米汞柱下进行8小时的血管紧张素转换酶抑制将几乎不会造成伤害。 与50毫米汞柱相比，(B)表明无创、低眼压会引起ONH基因表达的变化 低于但在质量上与那些具有损害性的较高眼压的人相似，以及(C)表明 老年动物暴露于血管紧张素转换酶抑制剂会比成年动物受到相同水平的压力造成更大的伤害。 动物。 具体目标2将显示：(A)在最初的、类似的暴露之后，第二次、损伤性ACEI的时间 将影响轴突损伤的可加性和(B)重复的、损伤性的ACEI的时机将影响ONH基因 表达和恢复。 具体目标3将证明：(A)重复血管紧张素转换酶抑制剂可用于模拟“慢性”青光眼 神经损伤，(B)压力导致视神经损伤的眼睛更容易发生后续的眼压 (C)眼压波动比相同水平的眼压波动产生更多的伤害。 眼压在相同时间内维持在稳定状态。 这些在未麻醉动物身上进行的研究使用的眼压水平，相对于正常的平均大鼠眼压，是 可与人类青光眼相提并论，并将提供人类这方面最准确的代表 在实验室大鼠身上可能出现的疾病。它们将为慢性粒细胞疾病的细胞机制提供独特的见解 青光眼视神经损害并允许研究这一慢性疾病以前无法接近的方面 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.