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NF-KB SIGNAL TRANSDUCTION IN BRAIN INJURY

脑损伤中的 NF-KB 信号转导

基本信息

批准号：
6642718
负责人：
Keith R Pennypacker
金额：
$ 21.18万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
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：
2000-09-30 至 2006-08-31
项目状态：
已结题

项目摘要

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，是细胞内抗凋亡信号转导的一个组成部分。肿瘤坏死因子受体-1刺激启动的免疫衍生细胞。核因子-kB在脑损伤后被激活，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这个转录因子。而核因子-kB在脑损伤中的作用一直备受争议，调查员的实验室发现脑损伤后存活神经元中核因子-kB p50的表达。他们观察到了一个 P50和p65表达的时程延长(伤后一至两周) 并提高NFkB DNA结合活性，表明NF-kB信号转导参与调节与再生相关的基因和修理。他们认为，脑损伤导致神经元中核因子-kB的激活存活的损伤，这种激活诱导生长的转录对促进细胞存活起决定性作用的因素。他们计划检测核因子-kB在大鼠海马区的表达和活性兴奋性毒性(海藻酸钙)、脑缺血(大脑中动脉)引起的损伤闭塞)和神经毒性(三甲基锡)，观察是否激活核因子-kB是脑损伤中的常见事件。含有kB基因的转基因小鼠反应启动子将被用来确定体内kB的激活大脑。核因子-kB在海马神经元损伤后存活中的作用通过p50(P105)基因敲除阻断核因子-kB转录而被识别老鼠和阿司匹林治疗。海马神经元计数将通过以下方式确定无偏细胞计数以确定对核因子-kB激活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RECOVERY，已被证明是核因子-kB驱动转录的靶基因在脑细胞培养中，但这还没有在活体大脑中得到证实损伤模型。他们将确定神经生长因子是否是核因子-kB在脑损伤中的共定位研究应用p50(P105)基因抑制脑损伤模型及核因子-kB的激活基因敲除小鼠和阿司匹林治疗。这些研究将确定核因子-kB在脑损伤及其修复再生过程中的作用流程。