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(申请人提供)：孤立性轴索卒中占美国每年发生的166,000例卒中的四分之三以上，但到目前为止还没有活体模型来分析这种卒中形式。我们建立了一种新的啮齿动物前部缺血性视神经病变(RAION)模型，该模型与人类AION直接相关。我们描述了轴索卒中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，雌激素显著减少了RAION后神经元的损失。我们假设：1)轴突缺血相关的脱髓鞘阻碍视神经修复。2)雌激素促进卒中后视神经恢复。我们的建议旨在回答三个相关的问题：1)RAION后在体内发生了哪些RGC轴突运输和胶质细胞的变化，从而导致永久性视神经损伤？为了回答这个问题，我们将使用Raion模型来定义早期视网膜和视神经应激相关的细胞事件，并确定视神经中风导致的视神经脱髓鞘和重塑的时间进程。这项工作将使用组织学、电生理学和分子方法进行。2)减少卒中后脱髓鞘能提高卒中后功能吗？在Raion模型中，我们将使用抗脱髓鞘药物，以确定减少卒中后脱髓鞘是否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学、立体定向逆行追踪、分子和组织学方法进行。 3)视神经损伤后给予雌激素是否也有神经保护作用？通过Raion模型、雌激素及雌激素抑制剂、电生理、组织学、立体定向和分子方法，我们将确定内源性雌激素的剂量、时间、性别和阻断的不同的影响。我们利用该模型获得的实验结果将使合理设计临床有效的神经保护策略，从而将缺血性轴索卒中的损害降至最低。