Neurotrophic Factor Deprivation and Neuronal Cell Death

超出所提供的空间。长期目标是了解神经元在正常发育过程中以及对损伤和疾病的反应中死亡的分子机制。这些信息不仅将提供关于神经系统形成中的基本事件的深刻见解，而且还可能导致发现在诸如脑和脊髓损伤、中风和神经退行性疾病等情况下阻断神经元死亡的治疗方法。该项目的具体目标是基于神经元细胞死亡通常需要死亡相关蛋白的转录依赖性合成的发现。拟议的研究将集中在两个转录途径，是因果关系参与神经元死亡引起的广泛的凋亡刺激，并已在本期间的支持的研究和实质性进展的主题。这些措施是：1）神经元凋亡细胞周期途径，其特征在于细胞周期蛋白依赖性激酶的不适当激活，这反过来导致通常被转录因子E2F抑制的死亡相关基因的去抑制。细胞培养研究将评估该途径被凋亡刺激物触发的机制，重点是细胞周期蛋白依赖性激酶4和细胞周期蛋白D1的调节。此外，实验将确定E2 F调节的转录因子B-和c-myB在死亡中的具体作用，以及死亡相关蛋白BIM受细胞周期途径调节的机制。最后，基因谱分析方法2）神经元凋亡JNK/cJun途径，其特征在于激活一条蛋白激酶链，最终磷酸化并激活转录因子c-JNK/cJun。研究将集中在表征支架蛋白POSH在该通路中的作用，并使用基因谱技术来鉴定该通路调控的死亡相关基因。性能现场=

EXCEED THE SPACE PROVIDED. The long term objective here is to understand the molecular mechanisms by which neurons die during normal development and in response to injury and disease. Such information will not only provide deep insight about a fundamental event in nervous system formation, but also potentially lead to discovery of therapeutic approaches to block neuron death in circumstances such as brain and spinal cord injuries, stroke and neurodegenerative disorders. The specific aims of this project are based on the finding that neuronal cell death generally requires transcription-dependent synthesis of death-associated proteins. The proposed studies will focus on two transcriptional pathways that are causally involved in neuronal death evoked by a wide range of apoptotic stimuli and that have been the subject of study and substantial progress during the present period of support. These are: 1) The neuronal apoptotic cell cycle pathway which is characterized by inappropriate activation of cyclin-dependent kinases that in turn leads to de-repression of death-associated genes that are normally repressed by the transcription factor E2F. Cell culture studies will evaluate the mechanisms by which this pathway is triggered by apoptotic stimuli, with emphasis on regulation of cyclin-dependent kinase 4 and cyclin D1. In addition, experiments will define the specific roles of the E2F-regulated transcription factors B- and c-myb in death as well as the mechanism by which the death-associated protein BIM is regulated by the cell cycle pathway. Finally, gene profiling methods (SAGE and gene microarrays) will be used to identify specific death-associated genes regulated by this pathway 2) The neuronal apoptotic JNK/cJun pathway which is characterized by activation of a chain of protein kinases that culminates in phosphorylation and activation of the transcription factor c-Jun. Studies will focus on characterizing the role of the scaffold protein POSH in this pathway and on using gene profiling technology to identify those death associated genes that this pathway regulates. PERFORMANCE SITE ========================================Section End===========================================