A functional approach to treating optic nerve stroke

描述（由申请人提供）：在美国每年发生的166,000例中风中，孤立性轴突中风占3/4以上，但到目前为止还没有体内模型来分析这种中风形式。我们建立了一种新的鼠类前缺血性视神经病变（rAION）模型，该模型与人类AION直接相关。我们描述了神经元和视神经在轴突中风后的反应。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以显著减少rAION后神经元的损失。我们假设：1)轴突缺血相关性脱髓鞘阻碍视神经修复。2)雌激素促进脑卒中后视神经恢复。我们的提案旨在回答三个相关问题：1)在体内，raon后RGC轴突转运和胶质细胞发生了哪些变化，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过程。这项工作将使用组织学、电生理学和分子方法进行。2)减少脑卒中后脱髓鞘是否能提高脑卒中后功能？在rAION模型中，我们将使用抗脱髓鞘药物，以确定减少中风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、立体定向逆行示踪、分子和组织学方法进行。

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.