Neuronal Plasticity and Recovery of Function After Stroke

描述（由申请人提供）：中风是一种导致神经元死亡和神经功能障碍的毁灭性疾病。通过针对Nogo-A蛋白的抗体治疗，可以中和成人中枢神经系统的抑制性质，从而增强大脑形成新神经元连接和恢复失去功能的固有能力。我们已经证明抗nogo - a免疫治疗可以改善成年大鼠缺血性脑卒中后的神经元可塑性和功能恢复。更好地了解抗nogo -A免疫疗法的机制将有助于改善临床应用的治疗方法。此外，由于中风在老年人中更为普遍，因此缺血性中风最好在模型中进行研究，该模型包含老年动物，正如我们在这里提出的那样。我们假设，干扰生长抑制蛋白Nogo-A可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大脑区域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验证我们的假设：具体目标1-确定中风后抗nogo - a免疫治疗是否会增加老年大鼠的轴突和树突可塑性。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。特定目的2-确定对侧前肢皮质是否介导中风和抗nogo - a免疫治疗后的恢复。我们将使用大卒中容量和小卒中容量来确定损伤大小对卒中恢复机制的影响，并通过检查诱发的前肢运动来使用皮质内微刺激来绘制剩余皮质组织。特异性目的3-确定全局或少突胶质细胞特异性Nogo-A敲除小鼠是否在缺血性卒中后表现出自发的神经可塑性，并进行基因组分析以确定卒中后可塑性的其他重要基因产物。这些研究的结果将通过对老年大脑修复机制的新见解，为缺血性脑损伤患者以及其他原因的脑损伤患者提供新的治疗方法，并为卒中后使用抗nogo - a免疫疗法的临床试验提供适当的设计。相关性：中风是一种毁灭性的疾病，它使数百万人的神经功能受损，并严重降低了他们的生活质量。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.