Neuronal Plasticity and Recovery of Function After Stroke

中风后神经元可塑性和功能恢复

• 批准号: 7559558
• 负责人: GWENDOLYN LOUISE KARTJE
• 金额: $ 24.91万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-15 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7559558
• 关键词: 129X1/SvJ Mouse; Adult; Affect; Age; Animals; Antibodies; Antibody Therapy; Area; Attention; Axon; Behavioral; Brain; Brain Injuries; Brain region; Catheters; Cervical spinal cord structure; Cessation of life; Clinical; Clinical Trials; Clinical Trials Design; Corpus striatum structure; Dendritic Spines; Disease; Europe; Exhibits; Forelimb; Funding; Gene Expression; Genomics; Golgi Apparatus; Grant; Hindlimb; Human; Immunohistochemistry; Immunotherapy; Individual; Injection of therapeutic agent; Ischemic Stroke; Knock-out; Knockout Mice; Lateral; Lead; Left; Length; Lesion; Location; Maintenance; Maps; Mediating; Methods; Modeling; Motor Cortex; Mouse Strains; Movement; Mus; Muscimol; Nature; Neurologic; Neuronal Plasticity; Neurons; Nogo protein; Oligodendroglia; Outcome; Pathway interactions; Patients; Phase I Clinical Trials; Process; Proteins; Publications; Quality of life; Rattus; Recovery; Recovery of Function; Red nucleus structure; Relative (related person); Sensorimotor functions; Spinal cord injury; Staining method; Stains; Stroke; Stroke Volume; Structure; Testing; Thalamic structure; Therapeutic; Therapeutic Intervention; Time; Tissues; Tracer; Translating; Translations; United States National Institutes of Health; Walking; aged; aging brain; biotinylated dextran amine; clinical application; design; disability; functional restoration; growth inhibitory proteins; human RTN4 protein; improved; in vivo; inhibitor/antagonist; insight; microstimulation; nerve supply; neurite growth; neuron loss; novel; novel therapeutic intervention; reinnervation; repaired; research study; stroke recovery; treatment duration

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.

描述（由申请人提供）：中风是一种毁灭性疾病，导致神经元死亡和神经疾病。大脑形成新的神经元连接和恢复功能的固有能力可以通过靶向蛋白质NOGO-A的抗体疗法中和成年CNS的抑制性来增强。我们已经表明，抗Nogo-A免疫疗法会导致成年大鼠缺血性中风后神经元可塑性和功能恢复。更好地理解抗Nogo-A免疫疗法的基本机制将导致改善临床使用的治疗方法。此外，由于中风在老年人中更为普遍，因此最好在模型中研究缺血性中风，该模型融合了老年动物，正如我们在此处提出的那样。我们假设干扰生长抑制蛋白NoGo-A会引起特定的基因组变化，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。我们将在以下特定目的中检验我们的假设：具体目标1-确定中风后的抗Nogo-A免疫疗法是否会导致老化大鼠的轴突可塑性增加。我们还将确定治疗的适当治疗时间，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品。具体目标2-确定相反的前肢皮层是否介导了中风和抗Nogo-A免疫疗法后的恢复。我们将同时使用大小卒中量来确定病变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绘制剩余的皮质组织。具体目标3-确定全球或少突胶质细胞特异性的Nogo-A基因敲除小鼠是否表现出缺血性中风后自发的神经塑性，并且还进行基因组分析以确定中风后可塑性的其他重要基因。这些研究的结果将导致新的治疗方法，使患有缺血性患者的功能失去功能，以及其他脑损伤的原因，通过对老年大脑的修复机制进行新的洞察力，并在中风后使用抗Nogo-A免疫疗法进行适当的设计，以适当设计将其转化为临床试验。相关性：中风是一种毁灭性的疾病，使数百万个人神经学障碍并严重降低了生活质量。我们发现了一种新型的免疫疗法，该免疫疗法将在成年大鼠缺血性中风后改善功能恢复，现在提出研究以阐明这种恢复的机制，以便将这些发现更好地转化为人类中风患者的有用疗法。