Immunotherapy to Improve Functional Outcomes after Chronic Stoke in the Aged

描述(由申请人提供)： 中风是一种破坏性的疾病，会导致神经元死亡和神经功能障碍。我们已经证明，通过中和Nogo-A蛋白的抗体疗法，中和成人中枢神经系统的抑制性质，可以增强大脑形成新的神经元连接和恢复中风后丧失的功能的固有能力。我们现在计划研究抗Nogo-A免疫疗法在促进慢性卒中损伤大鼠功能恢复和神经元可塑性方面的能力。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造成的患者。此外，了解中风慢性期给予抗Nogo-A免疫治疗后神经元可塑性的变化可能会为未来的临床应用带来改进的治疗方法。因此，我们假设，当对慢性中风受损的老年大鼠进行抗Nogo-A免疫治疗时，将导致改善功能结果，并增强对恢复至关重要的脑区的解剖可塑性。我们将在以下特定目标中验证我们的假设：特定目标#1-确定老年大鼠在缺血性中风后两个月接受抗Nogo-A免疫治疗是否能导致行为恢复。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，以加强这些结果的临床应用。具体目标#2-确定在老年大鼠缺血性卒中后两个月给予抗Nogo-A免疫治疗是否导致神经解剖可塑性。这一目标将使用神经解剖束追踪和高尔基-考克斯染色来检查对感觉运动恢复重要的区域的轴突和树突的可塑性。具体目标#3-使用运动学分析，确定中风受损的前肢的运动是否恢复到中风前的运动模式，或者是否在中风和抗Nogo-A免疫治疗后发生其他代偿策略。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。这些研究的结果将改变我们对慢性中风的看法，对神经康复领域产生巨大影响，即不再将缺陷视为“稳定的”或“固定的”，即使是长期受损的中风患者也有可能康复。

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.