APOPTOSIS IN TRAUMATIC SPINAL CORD INJURY

创伤性脊髓损伤中的细胞凋亡

基本信息

批准号：
6499457
负责人：
JOE E SPRINGER
金额：
$ 25.34万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-02-07 至 2004-01-31
项目状态：
已结题

项目摘要

The studies proposed in this grant application focus on identifying and characterizing the molecular signaling events involved in apoptotic cell death following traumatic spinal cord injury (SCI). Despite the recent evidence of widespread apoptosis in neurons and glia after SCI, the molecular components of the apoptotic pathway remain largely unknown. The proposed experiments will provide evidence of components in the apoptotic machinery responsible for initiating and executing this cell death process. In addition, experiments are proposed to demonstrate that blocking steps involved in the apoptotic cell death pathway provides neuroprotection and promotes functional recovery in acute SCI. We hypothesize that calcineurin-mediated BAD dephosphorylation is one of the initial upstream events in the apoptotic cascade and is linked to caspase-3 activation. Glutamate-induced Ca2+ influx leads to calcineurin activation and high levels of glutamate are released soon after SCI. Therefore, we will examine whether intrathecal injections of selective glutamate receptor agonists into uninjured spinal cord lead to calcineurin- mediated BAD dephosphorylation. In addition, we will demonstrate that injections of glutamate receptor antagonists reduce activation of the caspase-3 apoptotic cascade. Finally, the contribution of apoptosis to the functional deficits observed following SCI is not clear at this time. Therefore, we will treat injured animals with inhibitors targeting calcineurin and caspase-3 and use morphological, histological, and behavioral criteria to measure indices of apoptotic cell death and functional recovery. The outcome of these studies will have clear clinical implications for minimizing secondary neuronal and glial cell death and promoting recovery of function following SCI.

在本赠款申请中提出的研究集中于识别和表征创伤性脊髓损伤（SCI）后凋亡细胞死亡的分子信号传导事件（SCI）。尽管最近有SCI后神经元和神经胶质细胞凋亡的证据，但凋亡途径的分子成分仍然在很大程度上未知。提出的实验将提供负责启动和执行此细胞死亡过程的凋亡机制中组成部分的证据。此外，提出了实验以证明与凋亡细胞死亡途径中涉及的阻塞步骤可提供神经保护作用，并促进急性SCI的功能恢复。我们假设钙调蛋白介导的不良去磷酸化是凋亡级联反应的初始上游事件之一，并且与caspase-3激活相关。谷氨酸诱导的Ca2+涌入会导致钙调蛋白激活，而SCI后不久释放了高水平的谷氨酸。因此，我们将检查选择性谷氨酸受体激动剂的鞘内注射是否会导致脊髓不受伤害导致钙调蛋白介导的不良去磷酸化。此外，我们将证明注射谷氨酸受体拮抗剂减少了caspase-3凋亡级联反应的激活。最后，目前尚不清楚凋亡对SCI后观察到的功能缺陷的贡献。因此，我们将用靶向钙调神经酶和caspase-3的抑制剂治疗受伤的动物，并使用形态学，组织学和行为标准来测量凋亡细胞死亡和功能恢复的指标。这些研究的结果将具有明显的临床意义，以最大程度地减少次级神经元和神经胶质细胞死亡，并在SCI后促进功能的恢复。