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

中风后阻断轴突生长抑制剂促进功能修复

• 批准号: 7735575
• 负责人: Justine Overman
• 金额: $ 3.06万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7735575
• 关键词: Adult; Age; Area; Behavioral; Biopolymers; Blocking Antibodies; Blood - brain barrier anatomy; Clinical; Data; Drug Delivery Systems; Emerging Technologies; Ephrin-A5; Forelimb; Gene Expression; Genes; Goals; Growth Inhibitors; Heparin; Human; Hydrogels; Implant; Incidence; Infarction; Infusion procedures; Injury; Inorganic Sulfates; Intraventricular Infusion; Ligands; Location; Maintenance; Maps; Measures; Methods; Modeling; Monkeys; Motor; Mus; Myelin; Myelin Associated Glycoprotein; Nerve Root Avulsions; Neurons; Patients; Performance; Phase; Positioning Attribute; Process; Protein Engineering; Proteins; Recovery; Recovery of Function; Rodent; Role; Spinal cord injury; Stroke; System; Technology; Testing; Unspecified or Sulfate Ion Sulfates; Vibrissae; Work; aged; aging brain; axon growth; axonal sprouting; clinically relevant; disability; growth inhibitory proteins; improved; loss of function; neuronal growth; novel; post stroke; relating to nervous system; repaired; research study; response; somatosensory; statistics; targeted delivery; young adult

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.

描述（由申请人提供）：卒中诱导梗死周围和相邻皮质区域内的轴突发芽和皮质重组。该过程发生在啮齿动物、猴和人类中，并且与功能恢复相关（卡迈克尔，2006）。然而，生长抑制蛋白在轴突发芽发生的2-3周期间在梗塞周围皮层中表达，并且能够阻断这种发芽反应。轴突生长抑制剂阻断CMS损伤的其它模型中的神经元发芽和功能恢复，所述CMS损伤例如脊髓损伤和神经根撕脱（Schnell和Schwab，1993;米尔斯等人，2003年）。然而，除了NogoA蛋白（一种髓鞘相关的生长抑制剂）之外，关于中风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，在轴突发芽的过程中，在梗死周围皮层中独特地上调。重要的是，这些基因中的几个在中风后的梗死周围皮层中的老年脑中以甚至更高的水平上调，特别是肝配蛋白A5和髓鞘相关糖蛋白（MAG）。由于人类中风发病率随着年龄的增长而急剧增加，因此这两种分子能够阻断作为年龄函数的轴突发芽，因此是促进人类条件下轴突发芽的潜在重要靶标。在所提出的实验中，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中的ephrin A5和MAG，绘制功能皮层区域中轴突发芽的过程，并确定这些操作的行为恢复效果。肝配蛋白A5和MAG效应将使用植入中风腔内的生物聚合物基质进行修改，并全身递送经工程改造以穿过血脑屏障的蛋白质。这两种策略都具有临床相关潜力，可作为人类卒中的给药系统。这项研究的目的是促进中风后轴突发芽，局部皮质重新映射，并通过破坏生长抑制蛋白，EphrinAS和MAG，使用新的和临床相关的药物输送系统改善功能恢复。