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: 7753658
• 负责人: Justine Overman
• 金额: $ 3.08万
• 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/7753658
• 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(申请人提供)：中风可诱导梗死灶周围和邻近皮质区域的轴突萌发和皮质重组。这一过程发生在啮齿动物、猴子和人类身上，并与功能恢复相关(Carmichael，2006)。但是，在发生轴突萌发的2-3周期间，生长抑制蛋白在梗死区周围的皮质中表达，并处于阻止这种萌发反应的位置。在其他CMS损伤模型中，轴突生长抑制剂阻止神经元出芽和功能恢复，如脊髓损伤和神经根撕脱(Schnell and Schwab，1993；Mears等人，2003)。然而，除了一种髓鞘相关的生长抑制因子Nogoa蛋白外，关于中风轴突生长抑制物的研究很少。我们的实验室已经确定了一组轴突生长抑制物，它们在轴突萌发过程中在梗死区周围皮质中独特上调。重要的是，这些基因中的几个在中风后脑梗塞周围皮质的老年大脑中上调水平甚至更高，特别是ewitin A5和髓鞘相关糖蛋白(MAG)。由于人类中风的发病率随着年龄的增长而急剧增加，这两个分子处于阻止轴突萌发的年龄函数的位置，因此是促进人类条件下轴突萌发的潜在重要靶点。在拟议的实验中，我们将使用独特的和临床相关的蛋白质传递系统来阻断和诱导梗死区周围皮质中的肾上腺素A5和MAG，绘制功能皮质区轴突萌发的过程图，并确定这些操作的行为恢复效果。将使用植入卒中腔内的生物聚合物基质和系统性地输送经过改造以通过血脑屏障的蛋白质来改变EPhin A5和MAG的效果。这两种策略都具有作为人类卒中给药系统的临床相关潜力。这项拟议的研究的目标是促进卒中后轴突的萌发，局部皮质重新定位，并通过使用新型和临床相关的药物递送系统破坏生长抑制蛋白EPhinAS和MAG来促进功能恢复。