A functional approach to treating optic nerve stroke

治疗视神经中风的功能性方法

• 批准号: 7077651
• 负责人: STEVEN L BERNSTEIN
• 金额: $ 32.63万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7077651
• 关键词: apoptosis; confocal scanning microscopy; electrophysiology; estrogen inhibitor; estrogens; gene expression; histology; hormone regulation /control mechanism; ischemia; laboratory rat; myelinopathy; neuroprotectants; optic nerve; optic nerve disorder; polymerase chain reaction; stereotaxic techniques; stroke; terminal nick end labeling

DESCRIPTION (provided by applicant): Isolated axonal strokes comprise more than 3/4ths of the 166,000 strokes that occur in the US every year, but until now there has been no in-vivo model to analyze this stroke form. We have developed a new rodent anterior ischemic optic neuropathy (rAION) model of CNS axonal stroke that directly correlates with human AION. We have characterized the response of the neurons and optic nerve following axonal stroke. We have determined that rAlON results in optic nerve demyelination and loss of function. We have also found that estrogen significantly reduces the loss of neurons following rAION. We hypothesize that: 1) axon ischemia-associated demyelination blocks optic nerve repair. 2) Estrogen enhances post-stroke optic nerve recovery. Our proposal is designed to answer three related questions: 1) What RGC axonal transport and glial changes occur in-vivo following rAION, contributing to permanent optic nerve damage? To answer this question, we will use the rAION model to define early retina and optic nerve stress-related cellular events, and identify the time course of optic nerve demyelination and remodeling resulting from optic nerve stroke. This work will be performed using histological, electrophysiological, and molecular methods. 2) Can reducing post-stroke demyelination increase post-stroke function? With the rAION model, we will use anti-demyelinating drugs, to determine whether reducing post-stroke demyelination decreases permanent optic nerve damage and increases function. This work will be performed using electrophysiological, stereotactic retrograde tracing, molecular, and histological methods. 3) Does estrogen also exert neuroprotective effects when administered after optic nerve insult? With the rAION model, estrogen and estrogen inhibitors, electrophysiological, histological, stereotactic, and molecular methods, we will determine the effect of differences in dose, timing, sex, and blockade of endogenous estrogen. Our experimental results obtained with this model will enable rational design of clinically effective, neuroprotective strategies that can minimize ischemic axonal stroke damage.

描述（由申请人提供）：隔离的轴突中风包括每年在美国发生的166,000杆中的3/4以上，但到目前为止，尚无体内模型来分析这种中风形式。我们已经开发了一种新的啮齿动物前缺血性视神经病神经病（RAION）模型的CNS轴突中风模型，该模型与人类神经直接相关。我们已经表征了轴突中风后神经元和视神经的反应。我们已经确定Ralon会导致视神经脱髓鞘和功能丧失。我们还发现，雌激素可显着减少破裂后神经元的丧失。我们假设：1）轴突缺血相关的脱髓鞘会阻断视神经修复。 2）雌激素增强了势后视神经恢复。我们的建议旨在回答三个相关的问题：1）侵犯后体内发生了哪些RGC轴突运输和神经胶质变化，导致永久性视神经损害？为了回答这个问题，我们将使用Raion模型来定义早期的视网膜和与视神经应力相关的细胞事件，并确定视神经脱髓鞘和重塑的时间过程。这项工作将使用组织学，电生理和分子方法进行。 2）减少冲程后脱髓鞘可以增加中风后功能吗？使用Raion模型，我们将使用抗脱金正方药物来确定减少冲程后脱髓鞘是否会减少永久性视神经损伤并增加功能。这项工作将使用电生理，立体定向逆行追踪，分子和组织学方法进行。 3）雌激素在视神经侮辱后施用时是否会发挥神经保护作用？借助RAION模型，雌激素和雌激素抑制剂，电生理学，组织学，立体定向和分子方法，我们将确定内源性雌激素剂量，时机，性别和阻滞性差异的影响。我们通过此模型获得的实验结果将使可以理性地设计具有临床有效的神经保护策略，从而最大程度地减少缺血性轴突中风损伤。