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: 8044074
• 负责人: LLOYD A GREENE
• 金额: $ 51.72万
• 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 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8044074
• 关键词: Alzheimer' s Disease; Apoptotic; Binding; Biochemical Pathway; Cause of Death; Cell Culture Techniques; Cell Cycle; Cell Cycle Proteins; Cell Cycle Regulation Pathway; Cessation of life; Complex; Curiosities; Cyclin-Dependent Kinase 4; Development; Disease; Distal; Event; Figs - dietary; Genetic Transcription; Goals; HRK gene; Health; Injury; Knowledge; MAPK8 gene; Mediating; Modeling; Molecular; Nervous system structure; Neurites; Neurodegenerative Disorders; Neurons; Pathway interactions; Phosphotransferases; Play; Proteins; Puma; Research Design; Research Methodology; Role; Scaffolding Protein; Stimulus; Stroke; Testing; Trauma; combinatorial; deprivation; insight; neuron loss; neurotrophic factor; pro-apoptotic protein; promoter; protein complex; response; scaffold; tool; transcription factor; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): The overall goal of this project is to understand the mechanisms that govern death of neurons both in normal developmental and as a calamitous response to disease and injury. Understanding the former satisfies our curiosity and provides insight into how our nervous system is formed. Unraveling the latter may give us tools to treat neurodegenerative disorders, stroke and trauma. Our focus will be on the roles of transcription- dependent events and the pathways that regulate them in promoting neuron survival and death. Specifically, we will focus on two major pathways that mediate neuron death in a variety of circumstances relevant to both development and disease. These are the apoptotic "cell cycle" and "JNK" pathways. In each case, we will seek to extend (in both distal and proximal directions). our current knowledge about the component molecules that define and regulate these pathways. For the cell cycle pathway we will test the hypotheses that: a) The cell cycle regulatory protein Sei-1 plays a major role in initiating the pathway by interacting with and activating cyclin-dependent kinase 4 (Cdk4); b) Optimal promotion of neuron death occurs by a "coincidence" mechanism in which transcription factors regulated by the cell cycle, JNK and additional pathways simultaneously converge on promoters of pro-apoptotic proteins such as Bim and Puma. In contrast, the choice of the death proteins that are transcriptionally regulated (e.g. Bim vs. Puma) depends on the apoptotic stimulus and is dictated by a combinatorial transcription factor mechanism; c) The apoptotic proteins DP5(Hrk) and EglN3(Sm- 20) are also subject to regulation by the cell cycle pathway via the coincidence mechanism and these converge with Bim to promote efficient neuron death; and d) Components of the apoptotic cell cycle pathway uncovered in our cell culture models will also be relevant to neuron death caused by injury and disease and specifically, in Alzheimer's Disease.(AD). For the JNK pathway we will assess the hypotheses that: a) In healthy neurons, the apoptotic JNK pathway is suppressed by the POSH-related molecule POSH2 and the E3 ligase Cbl; that these promote destabilization of the required POSH scaffold protein and that in response to apoptotic stimuli, POSH2 and Cbl are lost/inactivated, leading to POSH stabilization and pathway initiation; b) Activation of the apoptotic JNK pathway requires translocation of its kinase components to the perinuclear region in a complex containing the scaffolds POSH and the JNK-interacting protein (JIP). In healthy neurons, JIP is localized to neurites and POSH levels are very low. In response to apoptotic stimuli, POSH is stabilized, binds JIPs and the complex (along with active JNKs) is actively translocated to the perinuclear region where it promotes death; and c) Components of the apoptotic JNK pathway uncovered in our cell culture models will also be relevant to neuron death caused by injury and disease and specifically, in Alzheimer's Disease (AD). These studies are anticipated to significantly enhance our understanding of how neurons die during development and in disease and to uncover potential targets and treatments to alleviate the latter.

描述（由申请人提供）：这个项目的总体目标是了解在正常发育和对疾病和损伤的灾难性反应中控制神经元死亡的机制。了解前者满足了我们的好奇心，并为我们了解神经系统的形成提供了洞见。解开后者可能会给我们提供治疗神经退行性疾病、中风和创伤的工具。我们的重点将放在转录依赖事件的作用和调控它们在促进神经元存活和死亡中的途径。具体来说，我们将关注在与发育和疾病相关的各种情况下介导神经元死亡的两种主要途径。这些是凋亡的“细胞周期”和“JNK”途径。在每种情况下，我们都将寻求延伸（在远端和近端方向）。我们目前对定义和调节这些途径的组成分子的知识。对于细胞周期途径，我们将测试以下假设：a)细胞周期调节蛋白Sei-1通过与细胞周期蛋白依赖性激酶4 （Cdk4）相互作用和激活，在启动该途径中起主要作用；b)神经元死亡的最佳促进是通过一种“巧合”机制发生的，在这种机制中，受细胞周期、JNK和其他途径调节的转录因子同时聚集在促凋亡蛋白（如Bim和Puma）的启动子上。相反，受转录调控的死亡蛋白的选择（例如Bim vs. Puma）取决于凋亡刺激，并由组合转录因子机制决定；c)凋亡蛋白DP5（Hrk）和EglN3（Sm- 20）也通过重合机制受到细胞周期通路的调控，并与Bim汇合，促进神经元有效死亡；d)细胞培养模型中发现的凋亡细胞周期通路的组成部分也与损伤和疾病引起的神经元死亡有关，特别是在阿尔茨海默病（AD）中。对于JNK通路，我们将评估以下假设：a)在健康神经元中，凋亡的JNK通路受到posh相关分子POSH2和E3连接酶Cbl的抑制；这些促进所需的POSH支架蛋白的不稳定，并且在凋亡刺激下，POSH2和Cbl丢失/失活，导致POSH稳定和途径启动；b)凋亡JNK通路的激活需要将其激酶组分易位到含有支架POSH和JNK相互作用蛋白（JIP）的复合物的核周区域。在健康的神经元中，JIP局限于神经突，POSH水平非常低。在对凋亡刺激的反应中，POSH是稳定的，结合jip和复合物（以及活性JNKs）主动转移到核周区域，在那里它促进死亡；c)细胞培养模型中发现的凋亡JNK通路成分也与损伤和疾病引起的神经元死亡有关，特别是阿尔茨海默病（AD）。这些研究有望显著增强我们对神经元在发育和疾病中如何死亡的理解，并发现潜在的靶点和治疗方法来减轻后者。