Cardiolipin as a Novel Target for Neuroprotection after Spinal Cord Injury

心磷脂作为脊髓损伤后神经保护的新靶点

• 批准号: 10084223
• 负责人: XIAO-MING XU
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10084223
• 关键词: Acute; Adult; Affect; Afghanistan; American; Antioxidants; Apoptosis; Apoptotic; Arachidonic Acids; Attenuated; Behavioral; CASP3 gene; Cardiolipins; Cell Death; Cell membrane; Chest; Clinical; Contusions; Data; Docosahexaenoic Acids; Dose; Freedom; Functional disorder; Generations; Guanosine Triphosphate Phosphohydrolases; In Vitro; Incidence; Injury; Inner mitochondrial membrane; Iraq; Lead; Linoleic Acids; Lipids; Mass Spectrum Analysis; Mechanics; Mediating; Medical; Medical History; Military Personnel; Mitochondria; Modeling; Molecular; Morphology; Nature; Neuronal Injury; Neurons; Optic Atrophy; Oxidative Stress; Oxides; Pathologic; Pathology; Pathway interactions; Phospholipids; Play; Polyunsaturated Fatty Acids; Process; Quality of life; Rattus; Reactive Oxygen Species; Recovery; Recovery of Function; Role; Signal Pathway; Signal Transduction; Spinal Cord; Spinal Cord Contusions; Spinal Injuries; Spinal cord injury; Spinal cord injury patients; Structure; System; Terrorism; Therapeutic; Time; Tissues; Translating; Traumatic Brain Injury; Treatment Efficacy; Veterans; War; base; clinically relevant; combat casualty; cytochrome c; dimer; effective therapy; functional disability; improved; in vivo; in vivo Model; lipidomics; member; mitochondrial dysfunction; neuron apoptosis; neuron loss; neuroprotection; novel; novel therapeutic intervention; operation; oxidation; peroxidation; repair strategy; repaired; restoration; wounded service member

Spinal cord injury (SCI) is among the most disabling conditions affecting wounded members of the U.S. military. Unfortunately, there has been no effective treatment available for SCI patients. It is, therefore, an urgent medical need to develop novel repair strategies to mitigate the devastating nature of SCI and to translate them clinically to improve quality of life of our veterans with SCI. Recently, a novel lipid signaling pathway, namely the cardiolipin (CL)-cytochrome c pathway, that control cell death/apoptosis has been identified. CL is a structurally unique dimeric phospholipid localized in the inner mitochondrial membrane where it is required for optimal mitochondrial function. CL is a preferred oxidation substrate in neuronal injury, is the only phospholipid in the mitochondria that undergoes early oxidation during apoptosis, and is an early target of reactive oxygen species (ROS) attack. Alteration of CL has been associated with mitochondrial dysfunction in a variety of pathological conditions. Using mass spectrometry-based lipidomics for the first time in SCI, we have generated preliminary data showing CL peroxidation and loss after SCI. Remarkably, XJB-5-131 (XJB),  a novel mitochondria-targeted antioxidant, administered at 30 min post-SCI significantly reduces tissue damage and improves behavioral recovery in adult rats. These data strongly suggest that CL alteration is a key mechanism that mediates injury-induced cell death and tissue damage. However, the role and mechanism of CL alteration in SCI remain unclear. Here, we hypothesize that CL alteration, including peroxidation and loss, is a central process that mediates spinal cord secondary injury, and that restoration of CL level may lead to neuroprotection and recovery of function after SCI. Using a rat spinal cord neuronal culture system in vitro and an adult rat thoracic contusive SCI model in vivo, we will determine 1) whether CL alteration induces mitochondrial dysfunction and neuronal death and whether such detrimental effects can be reversed by a novel mitochondrial targeted antioxidant XJB; 2) the molecular role of CL alteration in the signaling pathway of neuronal apoptosis after SCI and whether such CL alteration is sufficient to mediate secondary SCI; 3) whether abnormal mitochondrial dynamics also play a role in CL alteration-mediated cell death; and 4) an optimal dose and therapeutic time window of XJB on neuroprotection and functional recovery after rat contusive SCI.

脊髓损伤(SCI)是影响美国军队受伤人员的最严重的致残疾病之一。 不幸的是，目前还没有针对脊髓损伤患者的有效治疗方法。因此，这是一项紧迫的任务 医学需要开发新的修复策略来减轻脊髓损伤的破坏性并将其转化为 临床上提高退伍军人脊髓损伤患者的生活质量。最近，一种新的脂质信号通路，即 控制细胞死亡/凋亡的心磷脂(CL)-细胞色素c途径已被确定。CL是一种 结构上独特的二聚体磷脂定位于线粒体膜内，需要它 最优的线粒体功能。CL是神经元损伤的首选氧化底物，是唯一的磷脂 在线粒体中，在凋亡过程中经历早期氧化，是活性氧的早期目标 物种(ROS)攻击。CL的改变与多种疾病的线粒体功能障碍有关 病理情况。首次在脊髓损伤中使用基于质谱学的脂质组学，我们已经产生了 初步数据显示脊髓损伤后CL过氧化和丢失。值得注意的是，XJB-5-131(XJB)是一部小说 线粒体靶向抗氧化剂，在脊髓损伤后30分钟给予显著减少组织损伤和 改善成年大鼠的行为恢复。这些数据有力地表明CL改变是一种关键的机制 它介导了损伤导致的细胞死亡和组织损伤。然而，CL改变的作用和机制 在脊髓损伤中的作用仍不清楚。在这里，我们假设CL改变，包括过氧化和丢失，是一个中心 介导脊髓继发性损伤的过程，CL水平的恢复可能导致 脊髓损伤后的神经保护和功能恢复。利用大鼠脊髓神经元体外培养系统 建立成年大鼠在体胸部挫伤脊髓损伤模型，观察1)CL改变是否导致 线粒体功能障碍和神经元死亡以及这种有害影响能否被一种新的 线粒体靶向抗氧化剂XJB；2)CL改变在心肌梗死信号通路中的分子作用 脊髓损伤后神经元的凋亡以及这种CL改变是否足以介导继发性脊髓损伤；3) 线粒体动力学异常也在CL改变介导的细胞死亡中起作用；4)最佳剂量 治疗时间窗对大鼠挫伤脊髓损伤后神经保护和功能恢复的影响。

项目成果

Magnetic separation of peripheral nerve-resident cells underscores key molecular features of human Schwann cells and fibroblasts: an immunochemical and transcriptomics approach.

• DOI: 10.1038/s41598-020-74128-3
• 发表时间: 2020-10-28
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Peng K;Sant D;Andersen N;Silvera R;Camarena V;Piñero G;Graham R;Khan A;Xu XM;Wang G;Monje PV
• 通讯作者: Monje PV