APOPTOSIS INDUCED BY TRAUMATIC BRAIN INJURY

脑外伤引起的细胞凋亡

• 批准号: 6188005
• 负责人: ALAN Ira FADEN
• 金额: $ 23.77万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-15 至 2002-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6188005
• 关键词: apoptosis; behavioral /social science research tag; brain injury; cysteine endopeptidases; enzyme activity; enzyme inhibitors; immunocytochemistry; laboratory rat; memory; neuropsychological tests; psychomotor function; trauma

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.

描述（申请人的摘要）：中枢神经系统损伤后的神经元细胞损失 细胞凋亡和坏死的结果。 尽管细胞凋亡已 在实验性脑外伤 (TBI) 后的大脑中发现， 细胞凋亡在创伤后组织损伤及相关疾病中的关键作用 神经功能缺陷尚未确定。 而且，鲜为人知 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 哺乳动物细胞和主要研究人员最近证明 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。 初步的 我们实验室的研究还表明 caspase-3 的激活可能 是导致 TBI 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) TBI 导致与以下相关的 CPP32 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（caspase-1），减少创伤后细胞凋亡和相关 神经功能缺陷。 具体目标是： (1) 表征程度 和细胞凋亡的时间曲线并描绘所涉及的细胞类型 侧向液体冲击诱发 TBI 后受影响的大脑区域 老鼠； (2) 确定CPP32样的组织和细胞类型特异性变化 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 caspase 抑制剂减少创伤后 ​​caspase 的能力 活性和相关的神经元凋亡，以及相关的神经系统 TBI 后的缺陷，包括确定治疗窗 此类神经保护作用。