Neuronal Plasticity and Recovery of Function After Stroke

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。大脑形成新的神经元连接和恢复失去的功能的固有能力可以通过靶向蛋白质Nogo-A的抗体疗法中和成人CNS的抑制性质来增强。我们已经证明，抗Nogo-A免疫治疗导致成年大鼠缺血性卒中后神经元可塑性和功能恢复。更好地理解抗Nogo-A免疫治疗的机制将导致临床使用的治疗方法的改进。此外，由于中风在老年人中更普遍，因此最好在模型中研究缺血性中风，该模型包括老年动物，正如我们在这里提出的。我们假设，干扰生长抑制蛋白Nogo-A诱导特定的基因组变化，并通过增加对感觉运动功能重要的脑区的轴突和树突可塑性来增强中风后的功能恢复。我们将在以下具体目标中检验我们的假设：具体目标1-确定中风后抗Nogo-A免疫治疗是否导致老年大鼠轴突和树突可塑性增加。我们还将确定适当的治疗时间，并检查中风和抗Nogo-A治疗后发生的基因组变化，以便更好地了解我们模型中对中风恢复重要的其他重要基因产物。具体目标2-确定对侧病变前肢皮质是否介导中风和抗Nogo-A免疫治疗后的恢复。我们将使用大和小的每搏输出量来确定损伤大小对中风恢复机制的影响，并通过检查诱发的前肢运动来使用皮质内微刺激来映射剩余的皮质组织。具体目标3-确定整体或少突胶质细胞特异性Nogo-A敲除小鼠是否在缺血性中风后表现出自发的神经可塑性，并进行基因组分析以确定中风后可塑性的其他重要基因产物。这些研究的结果将导致新的治疗方法，通过对老年大脑中的修复机制提供新的见解，使患有缺血性以及其他脑损伤原因的患者恢复失去的功能，并导致适当的设计，用于在中风后使用抗Nogo-A免疫疗法转化为临床试验。相关性：中风是一种毁灭性的疾病，导致数百万人神经功能受损，严重降低他们的生活质量。我们已经发现了一种新的免疫疗法，可以改善成年大鼠缺血性中风后的功能恢复，现在我们提出研究来阐明这种恢复发生的机制，以便更好地将这些发现转化为对人类中风患者有用的治疗方法。

DESCRIPTION (provided by applicant): Stroke is a devastating disorder that leads to neuronal death and neurologic disability. The brain's inherent ability to form new neuronal connections and restore lost function can be enhanced by neutralizing the inhibitory nature of the adult CNS through antibody therapy targeting the protein Nogo-A. We have shown that anti-Nogo-A immunotherapy results in neuronal plasticity and functional recovery after ischemic stroke in adult rats. A better understanding of the mechanism underlying anti-Nogo-A immunotherapy would lead to improved therapeutic approaches for clinical use. Additionally, since stroke is more prevalent in the aged, ischemic stroke is best studied in a model, which incorporates the aged animal, as we propose here. We hypothesize that interfering with the growth inhibitory protein Nogo-A induces specific genomic changes and enhances functional recovery after stroke by increasing axonal and dendritic plasticity in brain regions important for sensorimotor function. We will test our hypothesis in the following specific aims: Specific aim 1- Determine whether anti-Nogo-A immunotherapy after stroke results in increased axonal and dendritic plasticity in the aged rat. We will also determine the appropriate treatment time for therapy, and examine genomic changes that occur after stroke and anti-Nogo-A therapy in order to better understand the other important gene products important for stroke recovery in our model. Specific aim 2- Determine whether contralesional forelimb cortex mediates recovery after stroke and anti-Nogo-A immunotherapy. We will use both large and small stroke volumes to determine the effects of lesion size on mechanisms of stroke recovery and also use intracortical microstimulation to map the remaining cortical tissue by examining evoked forelimb movements. Specific aim 3- Determine whether global or oligodendrocyte-specific Nogo-A knockout mice demonstrate spontaneous neuroplasticity after ischemic stroke, and also perform genomic analysis to determine other important gene products for plasticity after stroke. The results of these studies will lead to new therapeutic approaches to return lost function to patients suffering from ischemic, as well as other causes of brain damage by giving new insight into repair mechanisms in the aged brain, and lead to appropriate design for the translation into clinical trials using anti-Nogo-A immunotherapy after stroke. Relevance: Stroke is a devastating disorder that leaves millions of individuals neurologically impaired and severely decreases their quality of life. We have discovered a novel immunotherapy that will improve functional recovery after ischemic stroke in adult rats, and now propose studies to elucidate the mechanisms by which this recovery occurs in order to better translate these findings to a useful therapy for human stroke patients.