Augmentation of Plasma Membrane Repair for Treatment of Spinal Cord Injury

描述(申请人提供)：脊髓损伤导致功能缺陷，从轻微到危及生命，但临床上几乎没有有效的治疗方法。我们观察到创伤性脊髓损伤后神经元细胞体和轴突的损伤，这取决于损伤的严重程度。我们推测，这种损伤是由机械损伤引起的，正常的磷脂稳态被破坏，导致持续的损伤，最终导致不良的神经结局。我们的长期目标是开发临床相关的治疗方法，促进脊髓损伤后的膜修复。这个小型研究计划提案的具体目标是评估胞磷胆碱介导的质膜修复的效果和机制，胞磷胆碱是一种膜稳定剂，已被证明在许多中枢神经系统疾病模型中是有益的。总体的假设是，损伤引起的膜损伤对细胞存活和功能结果是不利的，但胞磷胆碱治疗可以通过促进膜的保存来减轻这些影响。具体地说，我们将使用临床相关的啮齿动物挫伤模型来1)确定胞二磷胆碱治疗脊髓损伤的剂量，定义为重新封闭细胞体、轴突和备用组织中受损的质膜的能力，2)评估胞二磷胆碱介导的修复的可能机制，以及3)评估胞二磷胆碱介导运动恢复的能力。我们认为胞磷胆碱通过降低脂质过氧化和磷脂酶A2的活性(两者都可能导致脊髓损伤后磷脂的分解)和增加磷脂的合成而导致膜的再密封。这些研究有望优化治疗方案，并开始确定脊髓损伤后膜损伤和修复的机制。拟议的研究描述了一个新的研究方向，并将提供有关靶向膜修复效果的关键数据，将指导未来的研究。 与公共卫生相关：迫切需要为脊髓损伤开发新的治疗策略，这种损伤会导致从轻微到危及生命的功能缺陷。在这项探索性研究中，我们建议靶向细胞膜修复作为一种可能的治疗方法。我们已经观察到创伤性脊髓损伤后的膜损伤，并假设磷脂的破坏有助于膜损伤，并可以通过添加膜稳定剂胞二磷胆碱来恢复。这些研究与公共健康直接相关，因为它们可能导致旨在为创伤性脊髓损伤和可能的其他神经疾病提供神经保护的新的治疗方法。

DESCRIPTION (provided by applicant): Spinal cord injury results in functional deficits that can range from mild to life threatening, but few effective treatments are clinically available. We have observed damage to neuronal cell bodies and axons after traumatic spinal cord injury that is dependent on the severity of the injury. We postulate that this damage is initiated by the mechanical injury and that normal phospholipid homeostasis is disrupted, leading to ongoing damage and ultimately negatively contributes to poor neurological outcome. Our long-term objective is to develop clinically relevant treatments that promote membrane repair following spinal cord injury. The specific objective of this small research program proposal is to assess the effects and mechanisms of plasma membrane repair mediated by citicoline, a membrane stabilizing agent that has been shown to be beneficial in many models of central nervous system disease. The overall hypothesis is that injury-induced membrane damage is detrimental to cell survival and functional outcome, but citicoline treatment can reduce these effects through facilitation of membrane preservation. Specifically, we will use a clinically relevant rodent contusion model to 1) determine a treatment dose of citicoline for spinal cord injury, defined by the ability to reseal compromised plasma membranes in cell bodies and axons and spare tissue, 2) assess possible mechanisms of citicoline-mediated repair, and 3) assess the ability of citicoline to mediate motor recovery. We propose that citicoline leads to membrane resealing by decreasing both lipid peroxidation and phospholipase A2 activity (both of which may contribute to phospholipid breakdown following spinal cord injury) and increasing phospholipid synthesis. These studies are expected to optimize a treatment regimen and begin to determine the mechanisms of membrane damage and repair following spinal cord injury. The proposed studies describe a new research direction and will provide critical data on the effects of targeted membrane repair that will guide future studies. PUBLIC HEALTH RELEVANCE: There is a critical need to develop new treatment strategies for spinal cord injury, which results in functional deficits that can range from mild to life threatening. In this exploratory study, we propose to target cell membrane repair as a possible therapy. We have observed membrane damage after traumatic spinal cord injury and hypothesize that phospholipid breakdown contributes to membrane damage and can be restored by adding citicoline, a membrane stabilizing agent. These studies are directly relevant to public health, as they may lead to novel treatment approaches aimed at neuroprotection for traumatic spinal cord injury and possibly other neurological disorders.