Axonal Growth in the Chronically Injured Spinal Cord

慢性损伤脊髓的轴突生长

• 批准号: 7056980
• 负责人: John D. Houle
• 金额: $ 11.36万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-08-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7056980
• 关键词: autologous transplantation; axon; biological signal transduction; combination therapy; confocal scanning microscopy; electronic stimulator; electrophysiology; enzyme therapy; extracellular matrix; fos protein; gene expression; immunocytochemistry; laboratory rat; laser capture microdissection; nervous system regeneration; nervous system transplantation; neuroimaging; neuronal guidance; neurons; neuroprotectants; neurotrophic factors; polymerase chain reaction; psychomotor function; spinal cord injury; therapy design /development; western blottings

DESCRIPTION (provided by applicant): Spinal cord injury (SCI) currently affects approximately 250,000 people in the U.S., with more than 10,000 new cases occurring each year. Currently, there is no cure for SCI. This study seeks to establish appropriate therapeutic interventions in a chronic SCI situation to support neuroanatomical and neurophysiological recovery. Work from the current funding period further defined the neuroprotective role of glial cell line-derived neurotrophic factor (GDNF) after an acute injury, the use of matrix-degrading enzymes to modify a spinal cord injury site, and the response of chronically injured neurons to neurotrophic factor (NTF) therapy after a second injury. This proposal will build upon this work and progress into new territory by addressing the significance of modulating an SCI site before applying strategies designed to accelerate axonal regrowth. We will also attempt to reduce some negative aspects of the neuronal response to injury by treating an acute injury with NTFs to heighten the regenerative effort of these neurons at chronic stages injury. The Specific Aims address the hypotheses that 1) degradation of the extracellular matrix prior to NTF treatment will increase axonal regeneration in the injured spinal cord, 2) acute neuroprotective therapy will enhance strategies for neuroregeneration in a chronic injury situation, and 3) regeneration enhanced by combined acute and chronic interventions can be characterized by changes in expression of regeneration-associated genes and/or activation of specific signaling pathways. Aim I will use an established cervical SCI-peripheral nerve (PN) graft model to test whether modulation of the extracellular matrix of the injured spinal cord prior to use of NTFs enhances axonal outgrowth from a PN graft and whether matrix-degrading enzymes effectively treat an established glial scar. Aim II examines acute neuroprotective treatment with GDNF to promote long-term survival and regeneration of chronically injured neurons. In Aim III, possible mechanisms underlying GDNF-enhanced regeneration after chronic injury will be examined by studying the expression of regeneration-associated genes and activated signaling pathways using laser microdissection, quantitative RT-PCR, and Western blot procedures. Overall, these experiments will provide fundamental information about cellular and molecular aspects of the neuronal and non-neuronal responses to long-term injury that will be instrumental in designing intervening therapies to repair the chronically injured spinal cord.

描述（由申请人提供）：目前，脊髓损伤（SCI）在美国影响约25万人，每年有10,000多例新病例。目前，无法治愈SCI。这项研究旨在在慢性SCI情况下建立适当的治疗干预措施，以支持神经解剖学和神经生理学恢复。当前资金期的工作进一步定义了急性损伤后神经胶质细胞系衍生的神经营养因子（GDNF）的神经保护作用，使用基质降解酶修饰脊髓损伤部位，以及修饰神经元对神经营养因子（NTF）损伤的反应。该建议将基于这项工作，并通过在应用旨在加速轴突再生的策略之前调节SCI站点的重要性来发展新领域。我们还将尝试通过使用NTF治疗急性损伤来减少神经元反应的某些负面反应，以加强这些神经元在慢性阶段损伤下的再生努力。具体目的是针对以下假设：1）NTF治疗前的细胞外矩阵降解将增加受伤受伤的脊髓中的轴突再生，2）急性神经保护疗法将增强慢性受伤状况中神经变化的策略，并通过良好的急性和慢性变化来提高慢性受损状况，并在急诊中加强效果。特定信号通路的激活。目的，我将使用已建立的宫颈Sci外外神经（PN）移植模型来测试在使用NTF之前调节受伤的脊髓的细胞外基质是否会增强PN移植物的轴突生长，并是否有效地治疗了固定的胶质性粘膜。 AIM II检查使用GDNF急性神经保护治疗，以促进长期生存和慢性损伤神经元的再生。在AIM III中，将通过研究与再生相关基因的表达来检查慢性损伤后GDNF增强再生的可能机制，并使用激光显微解剖，定量RT-PCR和Western Blot程序进行了激活的信号传导途径。总体而言，这些实验将提供有关神经元和非神经元反应对长期损伤的细胞和分子方面的基本信息，这将在设计中间疗法以修复长期受伤的脊髓。