Role of phospholipase A2 in spinal cord secondary injury

磷脂酶A2在脊髓继发性损伤中的作用

• 批准号: 7787702
• 负责人: XIAO-MING XU
• 金额: $ 33.69万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7787702
• 关键词: Acute; Affect; Apoptosis; Arachidonic Acids; Behavioral; Caspase; Cell Death; Cell membrane; Cessation of life; Cytosol; Cytosolic Phospholipase A2; Data; Development; Dose; Eicosanoids; Enzymes; Esters; Excitatory Amino Acids; Exhibits; Family; Fatty Acids; Free Radicals; Functional disorder; Glutamates; Hydrogen Peroxide; Hydrolysis; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Injury; Intervention; Isoenzymes; Lead; Lysophospholipids; Mechanics; Mediating; Mediator of activation protein; Membrane; Mitochondria; Modeling; Multiple Trauma; Mus; Neurons; Nonesterified Fatty Acids; Pathway interactions; Phospholipase A2; Phospholipids; Platelet Activating Factor; Play; Positioning Attribute; Production; Recovery; Recovery of Function; Role; Spinal Cord; Spinal cord injury; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; clinically relevant; cytokine; cytotoxic; cytotoxicity; deacylation; improved; inhibitor/antagonist; nervous system disorder; neuron loss; neuroprotection; neurotoxicity; novel; oxidation; preference; prevent; public health relevance; receptor

DESCRIPTION (provided by applicant): Role of phospholipase A2 in spinal cord secondary injury There are two mechanisms of damage to the spinal cord after injury: a primary mechanical injury and a secondary injury mediated by multiple injury mechanisms. To date, three injury mechanisms, i.e., inflammation, oxidation and excitatory neurotoxicity, are extensively studied following spinal cord injury (SCI). Since multiple mechanisms are involved, it is unlikely that blocking one particular mechanism would significantly prevent the course of secondary SCI. However, it is possible that these different mechanisms may share a central or convergence pathway to exert their detrimental effects. If so, blocking such a convergence pathway should result in greater anatomical and functional recovery than blocking a single pathway. A candidate molecule that could serve as a convergence mediator is the enzyme phospholipase A2 (PLA2). PLA2 is a diverse family of enzymes that hydrolyze the ester bond at the sn-2 position of phospholipids to produce a free fatty acid such as arachidonic acid (AA) and a lysophospholipid. These products are precursors of bioactive eicosanoids and platelet activating factor (PAF) that are well-known mediators of inflammation, oxidation and cytotoxicity. Additionally, PLA2 can attack cell membranes directly to induce neuronal and glial death. Although the downstream products of PLA2, such as AA, have been extensively studied, to our surprise, little is known concerning the role and mechanism of the PLA2 itself in traumatic SCI. Recently, we demonstrated, for the first time, that both the activity of total PLA2 and expression of cytosolic PLA2 (cPLA2; a subtype of PLA2) increased significantly following an acute contusive SCI (Liu et al., Ann Neurol 59:606-619, 2006). Remarkably, AACOCF3, a cPLA2 inhibitor, administered at 30 min post-SCI in mice significantly reduced tissue damage and improved behavioral recovery. Here, we propose a central hypothesis that PLA2 is a convergence molecule that mediates multiple injury pathways associated with the secondary SCI. If our hypothesis is correct, blocking PLA2 activation should induce inhibition of multiple injury pathways and, therefore, promotion of greater neuroprotection and functional recovery following SCI. Since cPLA2 is the most important PLA2 isozyme implicated in receptor-mediated release of AA, this application will focus on the role and mechanisms of cPLA2 action in mediating SCI. As such, the following three specific aims are proposed to determine 1) whether cPLA2 serves as a convergence molecule mediating the cytotoxic effects of free radicals, excitatory amino acids and inflammatory cytokines, 2) whether cPLA2 activation is both necessary and sufficient to mediate secondary SCI, and 3) the mechanism by which cPLA2 mediates secondary SCI with an emphasis being placed on the mitochondria dysfunction. Completion of this application may lead to the development of novel and effective strategies aimed at promoting greater anatomical and functional recoveries after SCI. PUBLIC HEALTH RELEVANCE: This application will test a central hypothesis that phospholipase A2 (PLA2) is a convergence molecule that mediates multiple injury mechanisms associated with secondary spinal cord injury (SCI). To test this hypothesis, we have proposed three specific aims to determine 1) whether cPLA2 serves as a convergence molecule that mediates the cytotoxic effects of free radicals, excitatory amino acids and inflammatory cytokines, 2) whether cPLA2 activation is both necessary and sufficient to mediate secondary SCI, and 3) the mechanism by which cPLA2 mediates secondary SCI with an emphasis being placed on the mitochondria dysfunction. We hope that, by completion of this application, we will identify a novel target for therapeutic intervention aimed at promoting greater anatomical and functional recoveries after SCI.

描述（由申请人提供）：磷脂酶A2在脊髓继发性损伤中的作用损伤后脊髓的损伤有两种机制：原发性机械损伤和由多种损伤机制介导的继发性损伤。迄今为止，脊髓损伤（SCI）后的三种损伤机制，即炎症、氧化和兴奋性神经毒性，被广泛研究。由于涉及多种机制，阻断某一特定机制不太可能显著阻止继发性脊髓损伤的进程。然而，这些不同的机制可能共享一个中心或趋同途径来发挥它们的有害影响。如果是这样的话，阻断这样一条趋同通路应该比阻断单一通路带来更大的解剖和功能恢复。可能作为聚合介质的候选分子是磷脂酶A2 （PLA2）。PLA2是一个多样化的酶家族，它水解磷脂sn-2位置的酯键，产生游离脂肪酸，如花生四烯酸（AA）和溶血磷脂。这些产物是生物活性类二十烷酸和血小板活化因子（PAF）的前体，它们是众所周知的炎症、氧化和细胞毒性介质。此外，PLA2可以直接攻击细胞膜，诱导神经元和胶质细胞死亡。尽管PLA2的下游产物，如AA，已被广泛研究，但令我们惊讶的是，PLA2本身在创伤性脊髓损伤中的作用和机制尚不清楚。最近，我们首次证明，急性挫伤性脊髓损伤后，总PLA2的活性和细胞质PLA2 （cPLA2； PLA2的一种亚型）的表达均显著增加（Liu et al., Ann Neurol 59:606- 619,2006）。值得注意的是，在小鼠脊髓损伤后30分钟给予AACOCF3（一种cPLA2抑制剂）可显著减少组织损伤并改善行为恢复。在这里，我们提出了一个中心假设，即PLA2是一种收敛分子，介导与继发性脊髓损伤相关的多种损伤途径。如果我们的假设是正确的，阻断PLA2激活应该会诱导多种损伤通路的抑制，从而促进脊髓损伤后更大的神经保护和功能恢复。由于cPLA2是参与受体介导的AA释放的最重要的PLA2同工酶，本应用将重点关注cPLA2在介导SCI中的作用和机制。因此，我们提出以下三个具体目的，以确定1)cPLA2是否作为一种收敛分子介导自由基、兴奋性氨基酸和炎症细胞因子的细胞毒性作用，2)cPLA2激活是否介导继发性脊髓损伤是必要的和充分的，以及3)cPLA2介导继发性脊髓损伤的机制，重点是线粒体功能障碍。这项应用的完成可能会导致新的和有效的策略的发展，旨在促进脊髓损伤后更大的解剖和功能恢复。