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

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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.