Immunotherapy to Improve Functional Outcomes after Chronic Stoke in the Aged

描述（由申请人提供）： 中风是一种毁灭性的疾病，导致神经元死亡和神经功能障碍。我们已经表明，大脑形成新的神经元连接和恢复中风后失去的功能的固有能力可以通过中和成人CNS的抑制性通过中和蛋白质Nogo-A的抗体治疗来增强。我们现在计划研究抗Nogo-A免疫疗法增强慢性中风受损大鼠的功能恢复和神经元可塑性的能力。这是一个令人兴奋和新颖的研究领域，可能会使更多患有慢性神经功能障碍的患者受益，即使是那些由中风以外的原因引起的患者。此外，了解在中风慢性阶段给予抗Nogo-A免疫治疗后神经元可塑性的变化可能会导致未来临床使用的治疗方法的改进。因此，我们假设，抗Nogo-A免疫治疗时，给予慢性中风受损的老年大鼠将导致改善功能的结果和增强解剖可塑性的大脑区域的重要恢复。我们将在以下具体目标中测试我们的假设：具体目标#1-确定在老年大鼠缺血性中风后两个月给予抗Nogo-A免疫疗法是否导致行为恢复。我们将在老年动物中使用感觉运动和认知恢复的行为测试，并研究长期结果，以提高这些结果的临床应用。具体目标#2-确定老年大鼠缺血性卒中后两个月给予抗Nogo-A免疫治疗是否会导致神经解剖学可塑性。这一目标将采用神经解剖束跟踪和高尔基-考克斯染色检查轴突和树突的可塑性在重要的感觉运动恢复的地区。具体目标#3-使用运动学分析确定中风受损前肢的运动是否恢复到中风前的运动模式，或者在中风和抗Nogo-A免疫治疗后老年大鼠中是否出现其他代偿策略。本提案的目的是测试我们的新型免疫疗法是否能改善慢性中风受损老年大鼠的功能恢复。这些研究的结果将对神经康复领域产生巨大的影响，改变我们看待慢性中风的方式，即不再将缺陷视为“稳定”或“固定”，即使是慢性受损的中风受害者也有可能康复。

DESCRIPTION (provided by applicant): Stroke is a devastating disorder that leads to neuronal death and neurologic disability. We have shown that the brain's inherent ability to form new neuronal connections and restore lost function after stroke can be enhanced by neutralizing the inhibitory nature of the adult CNS through antibody therapy that neutralizes the protein Nogo-A. We now plan to study the ability of anti-Nogo-A immunotherapy to enhance functional recovery and neuronal plasticity in the chronic stroke impaired rat. This is an exciting and novel area of research and may benefit many more patients who suffer with chronic neurologic disabilities, even those resulting from causes other than stroke. In addition, understanding changes in neuronal plasticity following anti-Nogo-A immunotherapy given at a chronic stage of stroke could lead to improved therapeutic approaches for future clinical use. Therefore, we hypothesize that anti-Nogo-A immunotherapy when given to chronic stroke-impaired aged rats will result in improved functional outcome and enhanced anatomical plasticity in brain regions important for recovery. We will test our hypothesis in the following specific aims: Specific Aim #1- Determine whether treatment with anti-Nogo-A immunotherapy results in behavioral recovery when given two months after ischemic stroke in the aged rat. We will use behavioral tests of sensorimotor and cognitive recovery in the aged animal and study long term outcomes in order to enhance the translation of these results to clinical use. Specific Aim #2- Determine whether treatment with anti-Nogo-A immunotherapy results in neuroanatomical plasticity when given two months after ischemic stroke in the aged rat. This aim will employ neuroanatomical tract tracing and Golgi-Cox staining to examine axonal and dendritic plasticity in areas important for sensorimotor recovery. Specific Aim #3- Determine if movements in the stroke-impaired forelimb return to pre-stroke movement patterns or if other compensatory strategies occur after stroke and anti-Nogo-A immunotherapy in aged rats using kinematic analysis. The goals of the present proposal are to test if our novel immunotherapy improves functional recovery in the chronic stroke-impaired aged rat. The results of these studies will have a tremendous impact on the field of neurorehabilitation by changing the way we view chronic stroke, i.e. no longer will a deficit be thought of as "stable" or "fixed", and recovery will be possible even for the chronically impaired stroke victim.