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.
