Augmentation of Plasma Membrane Repair for Treatment of Spinal Cord Injury

描述（由申请人提供）：脊髓损伤导致功能缺陷，范围从轻度到危及生命，但临床上几乎没有有效的治疗方法。我们已经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功能结局。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作用和机制，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。总体假设是损伤诱导的膜损伤对细胞存活和功能结果是有害的，但胞磷胆碱治疗可以通过促进膜保存来减少这些影响。具体而言，我们将使用临床相关的啮齿动物挫伤模型来1）确定胞磷胆碱用于脊髓损伤的治疗剂量，其由重新密封细胞体和轴突中受损质膜和备用组织的能力定义，2）评估胞磷胆碱介导的修复的可能机制，和3）评估胞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活性（这两者都可能导致脊髓损伤后磷脂分解）和增加磷脂合成来导致膜重新密封。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，并将提供关于靶向膜修复效果的关键数据，以指导未来的研究。 公共卫生相关性：目前迫切需要开发新的脊髓损伤治疗策略，脊髓损伤会导致从轻度到危及生命的功能缺陷。在这项探索性研究中，我们提出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，并假设磷脂分解有助于膜损伤，并可以通过添加胞二磷胆碱（一种膜稳定剂）恢复。这些研究与公共卫生直接相关，因为它们可能导致旨在保护创伤性脊髓损伤和其他神经系统疾病的新治疗方法。

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.