COX-2 Pathophysiology in Spinal Cord Injury

COX-2 脊髓损伤的病理生理学

• 批准号: 7194143
• 负责人: JOE E SPRINGER
• 金额: $ 29.07万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7194143
• 关键词: Address; Affect; Animals; Apoptosis; Apoptotic; Appearance; Behavior; Biochemical; Biological Assay; Cell Death; Cell Survival; Cells; Clinical; Coxibs; Demyelinations; Development; Distant; Enzymes; Event; Fiber; Functional disorder; Goals; Hour; Human; Individual; Injury; Limb structure; Locomotor Recovery; Measures; Mediator of activation protein; Modeling; Motor; Neuraxis; Numbers; Outcome; Outcome Study; Placement; Prostaglandin-Endoperoxide Synthase; Protein Isoforms; Role; Sensory; Site; Spinal cord injury; Testing; Therapeutic; Therapeutic Intervention; Tissues; United States; Week; behavior test; caspase-3; cell type; central nervous system injury; cyclooxygenase 1; cyclooxygenase 2; cytotoxic; design; functional improvement; improved; inhibitor/antagonist; kinematics; myelination; novel; research study; response

DESCRIPTION (provided by applicant): Traumatic spinal cord injury (SCI) results in a loss of voluntary motor and sensory function below the site of injury and affects some 300,000 individuals in the United States with ~10,000 new cases each year. Pathophysiological secondary responses following the initial insult promote additional and extensive damage occurring hours to weeks following injury and, therefore, are amenable to therapeutic interventions. Current therapies provide, at best, modest improvement of function and alternative strategies are warranted. The studies proposed in this application are designed to identify and better characterize the pathophysiological consequences of cyclooxygenase (COX) expression in traumatic spinal cord injury (SCI). Despite evidence of a pathological role for COX-2 induction in several models of central nervous system (CNS) injury, the role of the two COX isoforms (COX-1 and COX-2) as a mediators of cell death following SCI is unclear. The overall objective of the proposed experiments is to provide evidence that COX functions as an intracellular activator of cytotoxic oxidative damage and a mediator of apoptotic cell death following SCI. Specific Aim 1 will use pharmacological strategies and a number of biochemical assays to examine the contribution of COX-1 and COX-2 to oxidative damage. Studies in Specific Aim 2 will document conclusively, that COX expression occurs in cells that are undergoing apoptotic cell death following SCI (Aim 2a), and demonstrate that inhibiting the actions of either COX isoform reduces the appearance of apoptotic markers (Aim 2b). Studies proposed in Specific Aim 2 are a logical extension of Aim 1 as several studies have demonstrated that oxidative damage contributes to apoptotic cell death. Finally, Specific Aim 3 will demonstrate the therapeutic potential of blocking the actions of COX-1 or COX-2 in SCI. This will include a battery of behavioral tests that are highly sensitive to changes in sensorimotor and coordinated locomotor function. In addition, histological and morphological studies will be performed to document long term cell survival, improved tissue sparing at the injury epicenter, and enhanced myelination in fiber tracks distant to the site of injury. The outcome of these studies will document the pathophysiological involvement of COX expression in cell death following SCI, which has clear clinical implications for developing therapies in the treatment of SCI in humans.

描述（由申请人提供）：创伤性脊髓损伤 (SCI) 会导致损伤部位以下的自主运动和感觉功能丧失，影响美国约 300,000 人，每年约有 10,000 例新病例。初次损伤后的病理生理学继发反应会促进损伤后数小时至数周发生额外和广泛的损伤，因此适合治疗干预。目前的治疗充其量只能提供适度的功能改善，并且需要替代策略。本申请中提出的研究旨在识别和更好地表征创伤性脊髓损伤（SCI）中环氧合酶（COX）表达的病理生理学后果。尽管有证据表明 COX-2 诱导在几种中枢神经系统 (CNS) 损伤模型中具有病理作用，但两种 COX 亚型（COX-1 和 COX-2）作为 SCI 后细胞死亡介质的作用尚不清楚。所提出实验的总体目标是提供证据证明 COX 作为细胞毒性氧化损伤的细胞内激活剂和 SCI 后细胞凋亡的介质。具体目标 1 将使用药理学策略和多种生化检测来检查 COX-1 和 COX-2 对氧化损伤的贡献。具体目标 2 中的研究将最终证明，COX 表达发生在 SCI 后经历细胞凋亡的细胞中（目标 2a），并证明抑制任一 COX 同工型的作用可减少凋亡标记物的出现（目标 2b）。具体目标 2 中提出的研究是目标 1 的逻辑延伸，因为多项研究表明氧化损伤会导致细胞凋亡。最后，具体目标 3 将证明阻断 COX-1 或 COX-2 在 SCI 中的作用的治疗潜力。这将包括一系列对感觉运动和协调运动功能的变化高度敏感的行为测试。此外，还将进行组织学和形态学研究，以记录长期细胞存活、损伤中心组织保护的改善以及远离损伤部位的纤维轨迹增强的髓鞘形成。这些研究的结果将记录 COX 表达在 SCI 后细胞死亡中的病理生理学参与，这对于开发治疗人类 SCI 的疗法具有明确的临床意义。