NF-KB SIGNAL TRANSDUCTION IN BRAIN INJURY

脑损伤中的 NF-KB 信号转导

• 批准号: 6394232
• 负责人: Keith R Pennypacker
• 金额: $ 21.21万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6394232
• 关键词: DNA binding protein; SDS polyacrylamide gel electrophoresis; apoptosis; biological signal transduction; brain injury; developmental genetics; gene expression; gene induction /repression; genetic transcription; genetically modified animals; hippocampus; laboratory mouse; laboratory rat; nerve growth factors; nervous system regeneration; neurons; neurotoxicology; nuclear factor kappa beta; organ culture; transcription factor

DESCRIPTION (adapted from applicant's abstract): Nuclear factor-kB (NF-kB), a transcription factor, is a component of anti-apoptotic signal transduction in immune-derived cells initiated by tumor necrosis factor receptor-1 stimulation. NF-kB is activated in the brain after injury and many genes, such as growth factors and cytokines, associated with regeneration and repair are target genes for this transcription factor. While the function of NF-kB in brain injury has been controversial, the investigator's laboratory has discovered increased expression NF-kB p50 in neurons surviving brain injury. They have observed an extended time-course (one to two weeks after injury) of p50 and p65 expression and elevated NFkB DNA binding activity suggesting that NF-kB signal transduction is involved in regulating genes related to regeneration and repair. They propose that brain injury leads to activation of NF-kB in neurons surviving injury and that this activation induces the transcription of growth factors that play a decisive role in promoting cell survival. They plan to examine NF-kB expression and activity in the rat hippocampus in response to injury caused by excitotoxicity (kainite), ischemia (middle cerebral arterial occlusion) and neurotoxicity (trimethyltin) to observe whether activation of NF-kB is a common event in injury to the brain. Transgenic mice containing a kB responsive promoter will be used to determine kB activation in the in vivo brain. The role of NF-kB in neuronal survival in hippocampus after injury will be discerned by blocking NF-kB transcription using p50 (p105) gene knockout mice and aspirin treatment. Hippocampal neuronal counts will be determined by unbiased cell counting to determine if inhibition of NF-kB activation increases neuronal death. Nerve growth factor, an important gene in the brain's repair and recovery, has been shown to be a target gene of NF-kB-driven transcription in brain cell cultures but this has not been demonstrated in in vivo brain injury models. They will determine whether nerve growth factor is a target for NF-kB-driven transcription in brain injury using co-localization studies in these brain injury models and inhibiting NF-kB activation using p50 (p105) gene knockout mice and aspirin treatment. These studies will define the role of NF-kB in the process of brain injury and subsequent repair and regeneration processes.

描述（改编自申请人的摘要）：核因子-kB（NF-kB），a 转录因子，是抗凋亡信号转导的组成部分， 由肿瘤坏死因子受体-1刺激启动的免疫衍生细胞。 NF-kB在损伤后的大脑中被激活，许多基因，如生长 与再生和修复相关的因子和细胞因子是靶基因 对于这个转录因子。NF-κ B在脑损伤中的作用 研究人员的实验室发现， NF-kB p50在脑损伤存活神经元中的表达。他们观察到， p50和p65表达的延长时间过程（损伤后1 - 2周） 和升高的NF-κ B DNA结合活性，表明NF-κ B信号 转导参与调节与再生相关的基因， 修复.他们提出脑损伤导致神经元中NF-kB的激活 这种激活诱导了生长因子的转录， 这些因素在促进细胞存活方面起着决定性作用。他们计划 检测大鼠海马中NF-kB的表达和活性， 兴奋性毒性（红藻氨酸盐）、缺血（大脑中动脉 闭塞）和神经毒性（三甲基锡），以观察是否激活 NF-kB是脑损伤中常见的事件。含有kB的转基因小鼠 应答启动子将用于确定体内kB激活 个脑袋NF-kB在损伤后海马神经元存活中的作用 通过使用p50（p105）基因敲除阻断NF-kB转录来辨别 小鼠和阿司匹林治疗。海马神经元计数将通过 无偏细胞计数以确定NF-kB活化的抑制是否增加 神经元死亡神经生长因子，大脑修复中的重要基因 和恢复，已被证明是NF-κ B驱动转录的靶基因 但这尚未在体内脑中得到证实 伤害模型他们将确定神经生长因子是否是一个目标， 使用共定位研究在脑损伤中NF-kB驱动的转录 这些脑损伤模型和使用p50（p105）基因抑制NF-κ B活化 敲除小鼠和阿司匹林治疗。这些研究将确定 NF-kB在脑损伤及修复再生过程中的作用 流程.