APOPTOSIS INDUCED BY TRAUMATIC BRAIN INJURY

描述(申请人摘要)：中枢神经系统损伤后的神经细胞丢失 既有细胞凋亡，也有坏死。尽管细胞凋亡已经被 在实验性创伤性脑损伤(TBI)后的脑内表现 细胞凋亡在创伤后组织损伤中的关键作用及相关 神经缺陷尚未得到证实。此外，人们对此知之甚少。 关于中枢神经系统损伤后细胞凋亡的分子机制。一个 许多研究表明ICE或CPP32样半胱氨酸的作用 蛋白水解酶(分别称为caspase-1和caspase-3)与细胞凋亡 哺乳动物细胞和首席研究人员最近证明 Caspase-3的激活是小脑细胞凋亡的控制因素 颗粒细胞受到血清/K+联合剥夺。初步 我们实验室的研究还表明，caspase-3的激活可能 是脑挫伤后神经细胞凋亡的重要因素 老鼠。拟议的研究旨在解决以下问题 假设：(1)脑外伤引起CPP32样活性增加，与 神经元凋亡；(2)抑制caspase-3，但不抑制ICE样半胱氨酸 蛋白水解酶(caspase-1)，减少创伤后细胞凋亡，并与 神经缺陷。具体目标是：(1)表征程度 和凋亡的时间分布，并描绘所涉及的细胞类型 侧向液压冲击致大鼠脑损伤后脑区的变化 大鼠；(2)确定CPP32样蛋白的组织和细胞类型特异性变化 活动作为创伤严重程度和创伤后时间的函数，以及 将这种变化与神经细胞凋亡相关联；以及(3)检查 选择性半胱氨酸酶抑制剂降低创伤后半胱氨酸天冬氨酸酶的能力 活动性和相关神经细胞凋亡以及相关神经学 颅脑损伤后的缺陷，包括治疗窗口的确定 这样的神经保护作用。

DESCRIPTION (Applicant's abstract): Neuronal cell loss following CNS injury results from apoptosis as well as necrosis. Although apoptosis has been demonstrated in brain after experimental traumatic brain injury (TBI), a critical role for apoptosis in post-traumatic tissue damage and related neurological deficits has yet to be established. Moreover, little is known about the molecular mechanisms involved in apoptosis after CNS injury. A number of studies have suggested a role for ICE or CPP32-like cysteine proteases (Called caspase-1 and caspase-3, respectively) in apoptosis of mammalian cells and the principal investigator has recently demonstrated that activation of caspase-3 is a control factor in apoptosis of cerebellar granular cells subjected to combined serum/K+ deprivation. Preliminary studies from our laboratory also indicate that activation of caspase-3 may be an important factor contributing to neuronal apoptosis following TBI in rats. The proposed studies are intended to address the following hypotheses: (1) TBI causes increased CPP32-like activity associated with neuronal apoptosis ; (2) Inhibition of caspase-3, but not ICE-like cysteine proteases (caspase-1), reduces post-traumatic apoptosis and associated neurological deficits. Specific Aims are: (1) To characterize the degree and temporal profile of apoptosis and to delineate the cell types involved in affected brain regions following lateral fluid percussion induced TBI in rats; (2) To determine tissue and cell-type specific changes in CPP32-like activity as a function of injury severity and time after trauma, as well as to correlate such changes with neuronal apoptosis; and (3) To examine the ability of selective caspase inhibitors to reduce post-traumatic caspase activity and related neuronal apoptosis, as well as associated neurological deficits after TBI, including determination of the therapeutic window for such neuroprotective actions.