Neurotrophic Factor Deprivation and Neuronal Cell Death

神经营养因子剥夺和神经元细胞死亡

• 批准号: 6986733
• 负责人: LLOYD A GREENE
• 金额: $ 51.57万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-12-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6986733
• 关键词: Neurotrophic; Factor; Deprivation; Neuronal; Cell

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：这里的长期目标是了解神经元在正常发育过程中死亡的分子机制以及对损伤和疾病的反应。这些信息不仅将为神经系统形成的基本事件提供深入的见解，而且还可能导致发现在脑和脊髓损伤、中风和神经退行性疾病等情况下阻止神经元死亡的治疗方法。该项目的具体目标是基于发现神经元细胞死亡通常需要依赖于转录的死亡相关蛋白合成。拟议的研究将集中在两种转录途径上，这两种转录途径与各种凋亡刺激引起的神经元死亡有因果关系，并且在目前的支持期内已经成为研究的主题并取得了实质性进展。它们是：1)神经元凋亡细胞周期途径，其特征是细胞周期蛋白依赖性激酶的不适当激活，进而导致通常由转录因子E2F抑制的死亡相关基因的去抑制。细胞培养研究将评估凋亡刺激触发这一通路的机制，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，实验将明确e2f调控的转录因子B-和c-myb在死亡中的具体作用，以及死亡相关蛋白BIM受细胞周期通路调控的机制。最后，基因分析方法（SAGE和基因微阵列）将用于鉴定受该通路调控的特定死亡相关基因2)神经元凋亡JNK/cJun通路，其特征是激活一系列蛋白激酶，最终磷酸化和激活转录因子c-Jun。研究将集中在描述这一途径中支架蛋白POSH的作用，并利用基因谱技术鉴定这一途径所调节的死亡相关基因。