Post-Stroke Blockade of Axonal Growth Inhibitors to Promote Functional Repair

描述（由申请人提供）：中风引起梗死周围和邻近皮质区域的轴突发芽和皮层重组。这一过程发生在啮齿类动物、猴子和人类身上，并与功能恢复相关（Carmichael, 2006）。然而，在轴突发芽发生的2-3周期间，生长抑制蛋白在梗死周围皮层表达，并处于阻止这种发芽反应的位置。轴突生长抑制剂可阻断其他CMS损伤模型中的神经元发芽和功能恢复，如脊髓损伤和神经根撕脱（Schnell and Schwab, 1993; Mears et al., 2003）。然而，除了NogoA蛋白（一种髓鞘相关生长抑制剂）外，关于脑卒中轴突生长抑制剂的研究很少。我们的实验室已经确定了一组轴突生长抑制剂，在轴突发芽过程中，它们在梗死周围皮层中被上调。重要的是，这些基因中的一些在中风后的老年大脑梗死周围皮层中上调甚至更高水平，特别是ephrin A5和髓磷脂相关糖蛋白（MAG）。由于人类中风发病率随着年龄的增长而急剧增加，这两种分子可以阻止轴突发芽作为年龄的函数，因此是促进人类轴突发芽的潜在重要靶点。在拟议的实验中，我们将使用独特的和临床相关的蛋白质递送系统来阻断和诱导梗死周围皮层的ephrin A5和MAG，绘制功能皮质区域轴突发芽的过程，并确定这些操作的行为恢复效果。Ephrin A5和MAG的作用将通过植入中风腔内的生物聚合物基质和通过血脑屏障的系统蛋白质传递来改变。这两种策略都具有作为人类中风输送系统的临床相关潜力。本研究的目的是通过使用新型和临床相关的药物传递系统，通过破坏生长抑制蛋白EphrinAS和MAG，促进脑卒中后轴突萌发，局部皮层重新定位，并改善功能恢复。

DESCRIPTION (provided by applicant): Stroke induces axonal sprouting and cortical reorganization within peri-infarct and adjacent cortical areas. This process occurs in rodents, monkeys and humans and is correlated with functional recovery (Carmichael, 2006).However, growth inhibitory proteins are expressed in peri-infarct cortex during the 2-3 week period in which axonal sprouting occurs, and are in a position to block this sprouting response. Axonal growth inhibitors block neuronal sprouting and functional recovery in other models of CMS injury, such as spinal cord injury and nerve root avulsion (Schnell and Schwab, 1993; Mears et al., 2003). However, there has been little work on axonal growth inhibitors in stroke outside of the NogoA protein, a myelin-related growth inhibitor. Our lab has identified a set of axonal growth inhibitors that are uniquely upregulated in peri-infarct cortex during the process of axonal sprouting. Importantly, several of these genes are upregulated at even higher levels in the aged brain in peri-infarct cortex after stroke, especially ephrin A5 and myelin-associated glycoprotein (MAG). Because stroke incidence sharply increases with age in humans, these two molecules are in a position to block axonal sprouting as a function of age, and are thus potentially important targets for the promotion of axonal sprouting in the human condition. In the proposed experiments, we will use unique and clinically relevant protein delivery systems to block and induce ephrin A5 and MAG in peri-infarct cortex, map the process of axonal sprouting in functional cortical areas, and determine the behavioral recovery effect of these manipulations. Ephrin A5 and MAG effects will be modified using a biopolymer matrix that is implanted within the stroke cavity and with systemic deliver of proteins engineered to pass through the blood brain barrier. Both of these strategies have clinically relevant potential as delivery systems in human stroke. The goal of this proposed study is to promote axonal sprouting following stroke, local cortical re-mapping, and improved functional recovery by disrupting the growth inhibitory proteins, EphrinAS and MAG, using novel and clinically relevant drug delivery systems.