APOPTOSIS INDUCED BY TRAUMATIC BRAIN INJURY

描述（申请人摘要）：CNS损伤后的神经元细胞丢失 由细胞凋亡和坏死引起。 虽然细胞凋亡已经 在实验性创伤性脑损伤（TBI）后， 细胞凋亡在创伤后组织损伤及相关疾病中的重要作用 神经系统的缺陷还有待确定。 此外， CNS损伤后细胞凋亡的分子机制。 一 许多研究表明ICE或CPP 32样半胱氨酸的作用 蛋白酶（分别称为caspase-1和caspase-3）在细胞凋亡中的作用。 哺乳动物细胞，首席研究员最近证明， caspase-3激活是小脑细胞凋亡调控因子 颗粒细胞经受联合的血清/K+剥夺。 初步 我们实验室的研究还表明，caspase-3的激活可能 是脑外伤后神经细胞凋亡的重要因素， 大鼠 拟议的研究旨在解决以下问题 假设：（1）TBI导致与TBI相关的CPP 32样活性增加， 神经元凋亡;（2）抑制caspase-3，但不抑制ICE样半胱氨酸 蛋白酶（半胱天冬酶-1），减少创伤后细胞凋亡和相关的 神经缺陷 具体目的是：（1）表征程度 以及凋亡的时间分布，并描述所涉及的细胞类型 在受影响的脑区后，横向液压冲击诱导TBI， （2）测定CPP 32样细胞在组织和细胞类型上的特异性变化， 活动作为损伤严重程度和创伤后时间的函数，以及 将这些变化与神经元凋亡联系起来;（3）检查 选择性半胱天冬酶抑制剂减少创伤后半胱天冬酶的能力 活性和相关的神经细胞凋亡，以及相关的神经系统 TBI后的缺陷，包括确定治疗窗口， 这种神经保护作用。

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.