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.

项目摘要 了解眼内压（IOP）诱导的轴突损伤的细胞机制将有助于发展新的 保护视神经的青光眼治疗。我们受控的IOP（CEI）模型的高程产生光学 神经头（ONH）基因表达发生变化和视神经（ON）损伤，这些损伤与观察到的损伤 慢性模型。 RNASEQ时间课程分析表明，IOP产生了几种的早期激活 其组件的主要途径和特定恢复。我们现在已经开发了一种创建的方法 醒着的CEI（ACEI）使用内部插管在有意识的大鼠中暴露在有意识的大鼠中 可访问。这将使我们能够研究多年来发生的慢性青光眼事件 实验室环境的短时间。 在特定的目标1中，我们将（a）证明在40 mmHg处的8小时ACEI几乎不会受伤 与50 mmHg相比，（b）表明，较低的，较低的IOP会产生ONH基因表达变化 与受伤，更高的IOP和（c）所见的那些相似，但在质量上相似，（c）表明 与成人相同的压力，旧动物的ACEI暴露会产生更大的伤害 动物。 特定目标2将表明（a）初次接触后的第二秒，有害的ACEI的时机 将影响轴突损伤的添加性，（b）重复，有害ACEI的时间将影响ONH基因 表达和恢复。 特定目标3将表明（a）重复ACEI可用于建模“慢性”青光眼光学。 神经损伤，（b）具有压力引起的视神经损伤的眼睛更容易受到随后的IOP的影响 暴露于没有事先受伤的眼睛的暴露，（c）IOP波动造成的伤害比相同水平的伤害更多 IOP保持在稳定状态相同的持续时间。 这些在未经麻醉的动物中使用的研究使用的IOP水平相对于正常的平均大鼠IOP，是 与人类青光眼相当，将提供人类这一方面的最准确表示 实验室大鼠可能的疾病。他们将为慢性的细胞机制提供独特的见解 青光眼视神经损伤，允许研究此慢性的先前无法接近的方面 疾病。