Studies in Glaucomatous Optic Nerve Damage

青光眼视神经损伤的研究

• 批准号: 10436849
• 负责人: JOHN C MORRISON
• 金额: $ 47.91万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-04-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10436849
• 关键词: Address; Adult; Affect; Age; Aging; Anesthesia procedures; Angiography; Animals; Axon; Blindness; Cannulas; Cannulations; Chronic; Chronic Disease; Clinical; Conscious; Development; Disease; Elderly; Event; Exposure to; Eye; Female; Gene Expression; Gene Expression Alteration; Glaucoma; Goals; Health Sciences; Hour; Human; Injury; Laboratories; Laboratory Rat; Lead; Methods; Modeling; Norway; Optic Disk; Optic Nerve; Optic Nerve Injuries; Optical Coherence Tomography; Oregon; Outcome; Pathway interactions; Patients; Physiologic Intraocular Pressure; Physiologic pulse; Quantitative Reverse Transcriptase PCR; Rattus; Recovery; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Series; Testing; Time; Training; Universities; acronyms; anterior chamber; awake; axon injury; high intraocular pressure; human disease; insight; male; mature animal; nerve damage; new therapeutic target; novel therapeutics; pressure; response; tool; transcriptome sequencing

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.

项目概要 了解眼内压（IOP）引起的轴突损伤的细胞机制将有助于开发新的 我们的控制眼压升高 (CEI) 模型可产生视神经保护的青光眼治疗。 神经头 (ONH) 基因表达变化和视神经 (ON) 损伤与在 RNAseq 时间过程分析表明，IOP 会产生多种慢性模型的早期激活。 我们现在已经开发出一种创建方法。 使用外部留置前房插管对清醒大鼠进行清醒 CEI (aCEI) 暴露 这将使我们能够以相对容易的方式研究多年来发生的慢性青光眼事件。 实验室环境的时间较短。 在具体目标 1 中，我们将 (a) 证明 40 mmHg 下的 8 小时 aCEI 几乎不会造成伤害 与 50 mmHg 相比，(b) 显示无害的较低 IOP 将产生 ONH 基因表达变化 低于但在质量上类似于那些具有伤害性、较高眼压的情况，并且 (c) 表明 老年动物接触 aCEI 会比成年动物接触相同水平的压力时产生更大的伤害 动物。 具体目标 2 将表明 (a) 在初次类似暴露后发生第二次有害 aCEI 的时间 将影响轴突损伤的累加性，并且 (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”青光眼视神经 神经损伤，(b) 患有压力引起视神经损伤的眼睛将更容易受到随后的眼压的影响 (c) 眼压波动比相同水平的眼睛产生更多的伤害 IOP 在相同时间内保持稳定状态。 这些针对未麻醉动物的研究使用的 IOP 水平相对于正常的平均大鼠 IOP 为 与人类青光眼相当，并将提供人类这方面的最准确的表示 他们将为实验室老鼠的细胞机制提供独特的见解。 青光眼视神经损伤，并允许研究这种慢性疾病以前无法接近的方面 疾病。