A functional approach to treating optic nerve stroke

描述（由申请人提供）：孤立性轴突卒中占美国每年发生的166，000例卒中的3/4以上，但直到现在还没有体内模型来分析这种卒中形式。我们已经开发了一种新的啮齿动物前部缺血性视神经病变（rAION）模型的中枢神经系统轴突中风，直接与人类AION。我们的特点是神经元和视神经轴突中风后的反应。我们已经确定rAlON导致视神经脱髓鞘和功能丧失。我们还发现，雌激素显着减少rAION后神经元的损失。我们假设：1）轴突缺血相关的脱髓鞘阻断视神经修复。2)雌激素促进中风后视神经恢复。我们的建议旨在回答三个相关的问题：1）RGC轴突运输和胶质细胞的变化发生在体内后，rAION，有助于永久性视神经损伤？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，并确定视神经脱髓鞘和视神经卒中导致的重塑的时间过程。这项工作将使用组织学，电生理学和分子方法进行。2)减少卒中后脱髓鞘能增加卒中后功能吗？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学、立体定向逆行追踪、分子和组织学方法进行。 3)雌激素在视神经损伤后是否也有神经保护作用？利用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的剂量、时间、性别和阻断的差异的影响。我们的实验结果与此模型将使临床有效的合理设计，神经保护策略，可以最大限度地减少缺血性轴突卒中损伤。

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.