Drug-Enhanced Rehabilitation in Recovery from Stroke

中风恢复中的药物强化康复

• 批准号: 9039977
• 负责人: WILLIAM A. WOLF
• 金额: --
• 依托单位: EDWARD HINES JR VA HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9039977
• 关键词: Acute; Adult; Adverse effects; American; Amphetamines; Biochemical; Brain; Brain Injuries; Cardiovascular system; Caring; Clinical; Clinical Trials; Development; Disadvantaged; FGF2 gene; Fibroblast Growth Factor; Fibroblast Growth Factor Receptor 1; Fibroblast Growth Factor Receptors; Future; General Population; Genetic; Goals; Impairment; Injury; Inpatients; Ischemic Stroke; Left; Ligands; Mediating; Methods; Middle Cerebral Artery Occlusion; Modality; Motor; Motor Cortex; Motor Pathways; Neurites; Neuronal Plasticity; Neurons; Neuroprotective Agents; Outcome; Outpatients; Patients; Performance; Pharmaceutical Preparations; Phase; Physical activity; Physical therapy; Plasmids; Publishing; Quality of life; Rattus; Receptor Signaling; Recombinants; Recovery; Recovery of Function; Red nucleus structure; Regimen; Rehabilitation therapy; Role; Signal Transduction; Site; Stroke; Techniques; Testing; Therapeutic; Transgenes; Tyrosine Kinase Inhibitor; Up-Regulation; Veterans; Viral; Viral Vector; Work; chronic stroke; clinical application; clinical efficacy; cost; disability; environmental enrichment for laboratory animals; genetic approach; health administration; improved; in vivo; knock-down; mortality; motor function improvement; motor impairment; motor recovery; neurorestoration; noradrenergic; plasmid DNA; post stroke; pre-clinical; preclinical study; public health relevance; rehabilitation paradigm; rehabilitation strategy; relating to nervous system; small hairpin RNA; small molecule; stroke recovery; stroke rehabilitation; stroke therapy; therapeutic development; therapy design; translational study

 DESCRIPTION (provided by applicant): Motor impairment following ischemic stroke remains a leading cause of disability and reduced quality of life for our veterans and the general population. Physical therapy (PT) has been the mainstay of rehabilitation to restore motor function, but there is a clear need to improve and expand rehabilitation strategies. The use of adjunct medication has been extensively studied as one approach to enhance clinical outcomes. However, no drugs are presently established to be effective in enhancing rehabilitation-aided motor recovery. Studies from our lab and others suggest that certain drugs, such as amphetamine, hold such promise. Unfortunately, negative cardiovascular side effects associated with amphetamine have hindered its clinical application in stroke rehabilitation. Understanding the mechanisms underlying the rehabilitative potential of drugs will aid in the development of more effective, safer therapies. To this end the ability of amphetamine to enhance basic fibroblast growth factor (FGF2) signaling in the brain may be one such mechanism. In this proposal we will test the hypothesis that upregulation of FGF2 in the brain can significantly enhance motor recovery following ischemic stroke by facilitating neurite outgrowth from spared motor pathways through fibroblast growth factor receptor-1 (FGFR1)-related mechanisms. In aim I we will demonstrate that direct upregulation of FGF2 through intranasal application of plasmid DNA encoding FGF2 enhances motor recovery following permanent middle cerebral artery occlusion (MCAO) in rats. The importance of pairing treatment with physical therapy and the effects of delaying treatment on motor performance will also be assessed. Anterograde and retrograde tract tracing techniques will be used to ascertain the extent to which the unlesioned motor cortex sends new neuronal projections to once-denervated motor regions (i.e. the red nucleus). Biochemical studies will assess changes in transgene and native FGF2 expression and FGFR-related signaling implicated in neurite outgrowth. In Aim II we will extend our previously published work and determine the role of FGFR1 in mediating amphetamine-enhanced motor recovery and neural plasticity (i.e. neurite outgrowth) following permanent MCAO in rats. Two complementary approaches will be employed. A pharmacological approach will use the tyrosine kinase inhibitor, ponatinib, to globally inhibit FGFR signaling in the brain. A genetic approach will use a recombinant adeno-associated viral construct encoding for shRNA to FGFR1 to more specifically knock down FGFR1 in the unlesioned motor cortex, which we have previously established to be the site of new neuronal efferents. Aim III will follow the same intervention design as Aim II except the importance of FGFR signaling in mediating enhanced motor improvement and neurite outgrowth induced by plasmid-mediated upregulation of FGF2, as established in Aim I, will be tested. Taken together, the findings of this proposal will provide the framework for future mechanistic and translational studies to optimize rehabilitation paradigms for improved functional recovery following stroke.

 描述（由申请人提供）： 缺血性中风后的运动障碍仍然是退伍军人和普通人群的残疾和生活质量降低的主要原因。物理疗法（PT）一直是恢复恢复运动功能的支柱，但显然需要改善和扩大康复策略。辅助药物的使用已被广泛研究，作为增强临床结果的一种方法。但是，没有提出任何药物来有效地增强康复辅助运动的回收率。我们实验室和其他人的研究表明，某些药物（例如苯丙胺）具有这种希望。不幸的是，与苯丙胺相关的负心血管副作用阻碍了其在中风康复中的临床应用。了解药物康复潜力的基础机制将有助于开发更有效，更安全的疗法。为此，苯丙胺能够增强大脑中基本成纤维细胞生长因子（FGF2）信号的能力可能就是一种机制。在该提案中，我们将测试以下假设：通过支持从保留的运动途径通过成纤维细胞生长因子受体1（FGFR1）纠正的机制，通过支持从保留的运动途径的神经元出生来，大脑中FGF2的上调可以显着增强运动恢复。在目的中，我们将证明，通过鼻内施用编码FGF2的质粒DNA直接上调FGF2可增强大鼠永久性大脑中动脉闭塞（MCAO）后的运动恢复。还将评估配对治疗与物理治疗以及延迟治疗对运动性能的影响的重要性。顺行和逆行道追踪技术将用于确定未经疗法的运动皮层将新的神经元投影发送到曾经需要的运动区域（即红核）的程度。生化研究将评估在神经元出生中实施的转化和天然FGF2表达和与FGFR相关的信号的变化。在AIM II中，我们将扩展我们先前发表的工作，并确定FGFR1在大鼠永久性MCAO之后介导苯丙胺增强运动恢复和神经元可塑性（即神经元出现）中的作用。将采用两种完整的方法。一种药物方法将使用遗传方法将使用与shRNA至FGFR1编码的重组腺相关的病毒构建体，以更具体地击倒未经疗法的运动皮层中的FGFR1，我们以前已经确定，这是新神经元效率的部位。 AIM III将遵循与AIM II相同的干预设计，但FGFR信号在介导质粒介导的FGF2上调引起的增强运动改善和神经蛋白神经落生的重要性（AIM I）将被测试。综上所述，该提案的发现将为未来的机械和翻译研究提供框架，以优化康复范式，以改善中风后功能恢复。