Effects of CS GAG degradation on motor recovery post-SCI

CS GAG 降解对 SCI 后运动恢复的影响

• 批准号: 7062126
• 负责人: DENA R. HOWLAND
• 金额: $ 32.86万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7062126
• 关键词: axon; biotechnology; biotherapeutic agent; cats; cell growth regulation; cell population study; chondroitin sulfates; chordate locomotion; electrophysiology; hyaluronidase; immunocytochemistry; nervous system disorder chemotherapy; nervous system regeneration; neural plasticity; neurogenesis; neuromuscular function; neuronal guidance; neuroregulation; nonhuman therapy evaluation; protein degradation; protein protein interaction; protein structure function; proteoglycan; respiratory reflex; spinal cord injury

DESCRIPTION (provided by applicant): The failure of axonal growth in the adult spinal cord has been strongly associated with the presence of chondroitin sulfate proteoglycans (CSPGs) and enzymatic degradation of these molecules in vivo with the enzyme chondroitinase abc has been reported to increase axonal growth in rodent models of central nervous system damage. The central hypothesis to be tested is that intrathecal chondroitinase abc can promote axonal growth that leads to the reconstruction or augmentation of compromised host circuitry and results in enhanced motor function following spinal cord injury. Adult cats will receive low thoracic hemisections and be placed into one of three groups: hemisection-only, de-activated chondroitinase abc or active chondroitinase abc. Cats will be evaluated using a variety of locomotor tasks that demand the involvement of different levels of neural control. These will range from bipedal treadmill locomotion requiring only segmental networks to complex overground runways requiring specific descending supraspinal input. Thus, the type of behavioral recovery seen on these tasks will strongly suggest what neural substrates (pathways) are involved in the recovery process. Cats also will be tested for cough, which is an essential pulmonary defensive reflex that requires premotor input from the medulla. To our knowledge, this is the first effort to determine the influence of any therapeutic agent on spinal cord injury-induced impairment of cough. This will be done using nonterminal, as well as terminal, electrophysiological methods. Basic stains and immunohistochemistry will be used to characterize the lesion sites. Immunohistochemistry, tract tracing, and electrophysiological assays will be used to identify potential mechanisms of plasticity, and quantitatively assess axonal growth and the neuronal populations projecting to and/or past the lesion/treatment site. Results from these studies will allow us to identify the mechanisms of spontaneous recovery and how they may be enhanced or altered by chondroitinase abc treatment. The analyses of these two diverse motor behaviors (locomotion and cough) will allow us to differentiate selective from generalized recovery mechanisms induced by chondroitinase abc. This multi-system approach to recovery and plasticity after chronic spinal cord injury will provide a foundation on which other promising therapies for spinal cord injury can be tested (alone or in combination with chondroitinase abc).

描述（由申请人提供）：成年脊髓中轴突生长的失败与硫酸软骨蛋白蛋白聚糖（CSPGS）（CSPGS）的存在密切相关，并且这些分子在体内与软骨素酶ABC的体内分子降解相关已增加，据报道，酶促ABC已增加轴突神经损害的轴突增长。要测试的中心假设是，鞘内软骨蛋白酶ABC可以促进轴突生长，从而导致受损宿主电路的重建或增强，并在脊髓损伤后增强运动功能。成年猫将接受低胸腔半剖面，并将其放入三组之一中：仅半分裂，去激活的软骨蛋白酶ABC或活性软骨素酶ABC。将使用各种需要不同水平神经控制水平的运动任务来评估猫。这些范围从仅需要节段网络的两足动物跑步机运动到需要特定降落横向上输入的复杂地球跑道。因此，在这些任务上看到的行为恢复的类型将强烈表明恢复过程中涉及哪些神经底物（途径）。猫还将测试咳嗽，这是一种必不可少的肺部防御反射，需要从髓质中输入前运动。据我们所知，这是确定任何治疗剂对脊髓损伤引起的咳嗽损伤的影响的第一个努力。这将使用非末端以及末端电生理方法进行。碱性污渍和免疫组织化学将用于表征病变部位。免疫组织化学，道追踪和电生理测定法将用于识别可塑性的潜在机制，并定量评估轴突生长和投射到病变/治疗部位的神经元种群。这些研究的结果将使我们能够确定自发恢复的机制，以及如何通过软骨酶ABC治疗来增强或改变它们。对这两种不同的运动行为（运动和咳嗽）的分析将使我们能够将选择性与软骨素酶ABC诱导的广义恢复机制区分开。慢性脊髓损伤后这种多系统的恢复和可塑性方法将为其他有希望的脊髓损伤疗法（单独或与软骨素酶ABC结合）提供基础。