Chondroitin Sulfate Glycosaminoglycan: motor recovery post Spinal Cord Injury

描述（由申请人提供）：成年脊髓中轴突生长失败与硫酸软骨素蛋白聚糖（CSPG）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，这些分子在体内用软骨素酶abc酶促降解可增加轴突生长。要测试的中心假设是鞘内软骨素酶abc可以促进轴突生长，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增强。成年猫将接受低位胸半切术，并被分为三组：仅半切组、失活软骨素酶abc组或活性软骨素酶abc组。猫将使用各种运动任务进行评估，这些任务需要不同水平的神经控制。这些将包括从只需要节段网络的双足跑步机运动到需要特定的下行脊髓上输入的复杂地上跑道。因此，在这些任务中看到的行为恢复类型将强烈暗示恢复过程中涉及哪些神经基质（通路）。猫也将被测试咳嗽，这是一个基本的肺防御反射，需要运动前输入从延髓。据我们所知，这是首次尝试确定任何治疗药物对脊髓损伤引起的咳嗽损害的影响。这将使用非终末和终末电生理学方法完成。将使用碱性染色和免疫组织化学表征病变部位。将使用免疫组织化学、束示踪和电生理学测定来识别可塑性的潜在机制，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体。这些研究的结果将使我们能够确定自发恢复的机制，以及如何通过软骨素酶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区分软骨素酶abc诱导的选择性和一般性恢复机制。慢性脊髓损伤后恢复和可塑性的多系统方法将为测试其他有前途的脊髓损伤治疗方法（单独或与软骨素酶abc联合）提供基础。

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).