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）：成人脊髓轴突生长的失败与硫酸软骨素蛋白聚糖（CSPGs）的存在密切相关，据报道，在中枢神经系统损伤的啮齿动物模型中，这些分子在体内与软骨素酶abc酶降解会增加轴突生长。待验证的中心假设是鞘内软骨素酶abc可以促进轴突生长，从而导致受损的宿主电路的重建或增强，并导致脊髓损伤后运动功能的增强。成年猫将接受低胸半切开术，并被分为三组：仅半切开术组、去活化的软骨素酶abc组和活化的软骨素酶abc组。猫将被评估使用各种运动任务，需要参与不同水平的神经控制。这些范围将从只需要分段网络的两足跑步机运动到需要特定下行棘上输入的复杂地上跑道。因此，在这些任务中观察到的行为恢复类型将有力地表明哪些神经基质（途径）参与了恢复过程。猫也将接受咳嗽测试，这是一种必要的肺防御反射，需要髓质的运动前输入。据我们所知，这是第一次努力确定任何治疗剂对脊髓损伤引起的咳嗽损害的影响。这将使用非终端电生理方法和终端电生理方法来完成。基本染色和免疫组织化学将用于表征病变部位。免疫组织化学、尿道示踪和电生理分析将用于确定可塑性的潜在机制，并定量评估轴突生长和投射到和/或经过病变/治疗部位的神经元群。这些研究的结果将使我们能够确定自发恢复的机制，以及它们如何通过软骨素酶abc治疗增强或改变。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区分由软骨素酶abc诱导的选择性和广义恢复机制。这种慢性脊髓损伤后恢复和可塑性的多系统方法将为其他有希望的脊髓损伤治疗方法（单独或与软骨素酶abc联合）的测试提供基础。