COX-2 Pathophysiology in Spinal Cord Injury

描述（由申请人提供）：创伤性脊髓损伤（SCI）导致损伤部位以下的自主运动和感觉功能丧失，在美国影响约300，000人，每年约有10，000例新发病例。初始损伤后的病理生理学继发性反应促进损伤后数小时至数周发生的额外和广泛的损伤，因此适合于治疗干预。目前的治疗提供，最好的，适度的改善功能和替代策略是必要的。本申请中提出的研究旨在鉴定和更好地表征创伤性脊髓损伤（SCI）中环氧合酶（考克斯）表达的病理生理学后果。尽管有证据表明考克斯-2诱导在几种中枢神经系统（CNS）损伤模型中的病理作用，但两种考克斯亚型（考克斯-1和考克斯-2）作为SCI后细胞死亡的介导物的作用尚不清楚。所提出的实验的总体目标是提供证据证明考克斯作为细胞毒性氧化损伤的细胞内激活剂和SCI后凋亡性细胞死亡的介体发挥作用。具体目标1将使用药理学策略和许多生化测定来检查考克斯-1和考克斯-2对氧化损伤的贡献。具体目标2的研究将最终证明，考克斯表达发生在SCI后发生凋亡性细胞死亡的细胞中（目标2a），并证明抑制任何一种考克斯亚型的作用都会减少凋亡标志物的出现（目标2b）。具体目标2中提出的研究是目标1的逻辑延伸，因为几项研究已经证明氧化损伤有助于凋亡细胞死亡。最后，具体目标3将证明在SCI中阻断考克斯-1或考克斯-2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、损伤中心组织保留的改善以及远离损伤部位的纤维轨迹中髓鞘形成的增强。这些研究的结果将记录考克斯表达在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。

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.