Mechanisms underlying Netrin-1-mediated functional recovery after stroke

Netrin-1 介导的中风后功能恢复的机制

• 批准号: 8202149
• 负责人: JIALING LIU
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8202149
• 关键词: Adenosine; Adenosine A2B Receptor; Adjuvant; Adverse effects; Affect; Amphetamines; Animal Experimentation; Animal Model; Apoptotic; Behavioral; Blood; Blood Cells; Blood Vessels; Bone Marrow Transplantation; Brain; Brain Ischemia; Capsid Proteins; Cells; Cerebral Ischemia; Chemicals; Chronic; Clinical; Clinical Trials; Colon Carcinoma; Data; Dependovirus; Development; Disease; Enhancing Lesion; Future; Gene Transduction Agent; Gene Transfer; Infarction; Infection; Inflammation; Injury; Ischemic Stroke; Lead; Mediating; Motor; Mus; Neuraxis; Neuronal Plasticity; Outcome; Pathway interactions; Patients; Peptides; Perfusion; Play; Production; Proteins; Recovery; Recovery of Function; Regimen; Rehabilitation therapy; Reporting; Role; Safety; Secondary Prevention; Signal Transduction; Stroke; Structure; Synaptic plasticity; Taxes; Testing; Tissues; Training; Treatment Efficacy; Vascular Endothelial Growth Factors; Vascular Permeabilities; Vascular System; Vertebral column; adeno-associated viral vector; base; cell motility; clinical application; density; disability; functional restoration; gene therapy; hemodynamics; human NTN1 protein; improved; migration; neogenin; nerve stem cell; netrin receptor; netrin-1; neuroinflammation; neuroregulation; neurovascular unit; novel; overexpression; post stroke; preclinical study; receptor; rehabilitation strategy; relating to nervous system; research study; stroke rehabilitation; stroke therapy; therapeutic target; transgene expression; vector; white matter

DESCRIPTION (provided by applicant): Stroke remains the leading cause of long-term disability in the US. To enhance post stroke functional recovery, appropriate rehabilitation strategy is in dire need. The concept of neurovascular unit and the multiple mechanisms involved in secondary injury is changing our approach in stroke therapy. Following focal cerebral ischemia, although the tissue perfusion in the peri-infarct cortex improved gradually in a distance-dependent manner, it is never fully restored even months after. It is evident that the recovery of local hemodynamics also affected the recovery of spine density, and ultimately, synaptic plasticity. Our preliminary results establish that functional restoration induced by AAV-Netrin-1 gene therapy is associated with an increase in vascular density in the peri-infarct cortex, which could be related to netrin-1's proangiogenic effect or prevention of secondary injury. Based on these promising results and the diverse effects of netrin-1 in anti-inflammation and neuroplasticity induction, we would like to extend our study to further investigate the therapeutic efficacy of netrin-1 and underlying signaling mechanisms in reducing inflammation and promoting neuroplasticity in the context of brain ischemia and functional recovery. The following specific aims are proposed: Aim 1. Test the hypothesis that netrin-1 gene transfer reduces post stroke chronic neuroinflammation via adenosine 2B receptor. To distinguish the contribution of blood versus endothelial A2B receptors, we will use bone marrow transplants to create chimeric mice. Aim 2 will test the hypothesis that netrin-1 gene transfer enhances neural stem cell migration in the ischemic peri-infarct and white matter via specific netrin-1 receptors. Aim 3 will test the hypothesis that netrin-1 gene transfer augments the neuroplasticity inducing effect of amphetamine and rehabilitation. Proof-of-concept data collected here may lead to the development of netrin-1 as a novel target for stroke therapy in promoting functional recovery. PUBLIC HEALTH RELEVANCE: Stroke remains the leading cause of long-term disability in the US. Although most stroke patients make some degree of recovery in weeks to months after the insult, it has become increasingly apparent that promoting recovery in the stroke patients requires appropriate rehabilitation therapy. Despite the progress made in animal research, clinical trials have generally failed to demonstrate the robust and significant improvement in patient outcome necessary for clinical application. Due to the complexity of our brain, multiple cascades of pathways are involved in secondary injury and recovery. There is a growing recognition that therapies targeting more than one pathway are needed to improve patient outcome. Our preliminary study suggests that netrin-1 gene therapy improves the neural structure and function. This proposed study will establish proof-of-concept evidences for future development of adjuvant therapeutics targeting netrin-1 in stroke rehabilitation.

描述（由申请人提供）： 中风仍然是美国长期残疾的主要原因。为了促进中风后功能恢复，迫切需要适当的康复策略。神经血管单元的概念和继发性损伤涉及的多种机制正在改变我们中风治疗的方法。局灶性脑缺血后，尽管梗塞周围皮层的组织灌注以距离依赖的方式逐渐改善，但即使几个月后也不会完全恢复。显然，局部血流动力学的恢复也影响了脊柱密度的恢复，并最终影响了突触可塑性。我们的初步结果表明，AAV-Netrin-1 基因治疗诱导的功能恢复与梗塞周围皮层血管密度的增加有关，这可能与 netrin-1 的促血管生成作用或预防继发性损伤有关。基于这些有希望的结果以及 netrin-1 在抗炎和神经可塑性诱导中的多种作用，我们希望扩展我们的研究，以进一步研究 netrin-1 的治疗功效以及潜在的信号传导机制在减少炎症和促进神经可塑性方面的作用。脑缺血和功能恢复的背景。提出以下具体目标： 目标 1. 检验 netrin-1 基因转移通过腺苷 2B 受体减少中风后慢性神经炎症的假设。为了区分血液与内皮 A2B 受体的贡献，我们将使用骨髓移植来创建嵌合小鼠。目标 2 将检验这样的假设：netrin-1 基因转移通过特定的 netrin-1 受体增强缺血性梗塞周围和白质中的神经干细胞迁移。目标 3 将检验 netrin-1 基因转移增强安非他明和康复的神经可塑性诱导作用的假设。这里收集的概念验证数据可能会导致 netrin-1 发展成为中风治疗促进功能恢复的新靶点。 公共卫生相关性： 中风仍然是美国长期残疾的主要原因。尽管大多数中风患者在受到损伤后数周至数月内即可得到一定程度的恢复，但越来越明显的是，促进中风患者的康复需要适当的康复治疗。尽管动物研究取得了进展，但临床试验通常未能证明临床应用所需的患者结果的稳健和显着改善。由于我们大脑的复杂性，二次损伤和恢复涉及多个级联通路。人们越来越认识到，需要针对多种途径的治疗来改善患者的治疗结果。我们的初步研究表明 netrin-1 基因疗法可改善神经结构和功能。这项拟议的研究将为未来开发针对中风康复中 netrin-1 的辅助疗法提供概念验证证据。