Fos, Jun & synaptic plasticity

福斯，君

• 批准号: 6849771
• 负责人: MANI RAMASWAMI
• 金额: $ 34.09万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-15 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6849771
• 关键词: AP1 protein; Drosophilidae; JUN kinase; active sites; behavioral /social science research tag; cAMP response element binding protein; drug addiction; gene expression; gene mutation; genetic regulation; genetically modified animals; microarray technology; motor neurons; nerve /myelin protein; neural plasticity; neuropsychology; phosphorylation; synapses; transcription factor

DESCRIPTION (provided by applicant): Drug addiction, long-term memory and other lasting behavioral changes derive from plasticity of underlying neural circuits, driven by activity-regulated gene expression. Recent behavioral analyses demonstrate critical roles for two transcription factors, CREB and AP1 (usually a dimer of Fos and Jun) in regulating cocaine addiction. Induction of FosB, a dominant-negative Fos isoform, in rodent nucleus accumbens causes long-term behavioral sensitization and craving for cocaine; in contrast, induction of CREB reduces drug-reward by inducing adaptation to higher levels of cocaine. Despite the obvious importance of AP1 and CREB for behavioral plasticity, little is known about the mechanism of their action. Our recent observations are consistent with the unexpected, important hypothesis that AP1 acts upstream of CREB at the top of the hierarchy of known plasticity-associated transcription factors. While testing this hypotheses, this proposal aims to: a) more completely elaborate cellular functions of AP1; and b) identify molecular mechanisms that operate upstream and downstream of AP1. In the short term, the work will provide a description of cellular biological consequences of AP1 manipulations, and outline the hierarchies and relationships among regulatory proteins, like AP1, CREB and MAP kinases that initiate plasticity processes. In the longer term, effector molecules that mediate the processes of synaptic change will be identified and their functions analyzed. Drosophila melanogaster is an excellent model organism for these analyses. The commonality of underlying mechanisms involved in plasticity regulation in mammals and insects is indicated by the functional conservation of almost all known regulators of plasticity in both phyla. However, the rate of progress of the proposed analyses in Drosophila is much faster, facilitated not only by its short generation time and facility for genetics, but also by novel resources from Drosophila genome projects, microarray technologies and newly developed procedures for gene disruption, perturbation and replacement in vivo. The proposed experiments address an area of fundamental importance in synaptic remodeling events that underlie behavioral change. The work is particularly significant because it addresses the function of Fos and Jun, two critical regulators of drug addiction. In addition, by identifying activity-regulated neuronal proteins the program may contribute new, molecular markers of plasticity processes that underlie addiction. Finally, results from these experiments may identify and validate new molecules to target for pharmacological therapy.

描述（由申请人提供）： 药物成瘾，长期记忆和其他持久的行为变化源于基因表达的基础神经回路的可塑性。最近的行为分析表明，两个转录因子CREB和AP1（通常是FOS和JUN的二聚体）在调节可卡因成瘾中的关键作用。在啮齿动物核中诱导FOSB（一种显性阴性的FOS同工型）引起伏隔核引起的长期行为敏化和对可卡因的渴望。相反，CREB的诱导通过诱导更高水平的可卡因来降低药物奖励。尽管AP1和CREB对行为可塑性的重要性显而易见，但对其作用的机制知之甚少。我们最近的观察结果与意想不到的重要假设一致：AP1在CREB上游起作用在已知可塑性相关的转录因子的层次结构顶部。在测试该假设的同时，该提案的目的是：a）更完整的AP1的细胞功能； b）确定在AP1上游和下游运行的分子机制。在短期内，这项工作将提供AP1操纵的细胞生物学后果的描述，并概述了启动可塑性过程的调节蛋白（如AP1，CREB和MAP激酶）之间的层次结构和关系。从长远来看，将确定介导突触变化过程的效应分子并分析其功能。果蝇Melanogaster是这些分析的出色模型生物。哺乳动物和昆虫可塑性调节涉及的基本机制的共同点通过功能保存在两个门中几乎所有已知的可塑性调节剂。然而，果蝇中提出的分析的进度速度要快得多，不仅是由于其短生成时间和遗传学的设施，而且还促进了果蝇基因组项目，微阵列技术的新资源，以及新开发的基因扰动，扰动和替代的过程。拟议的实验介绍了行为变化构成的突触重塑事件中基本重要性的领域。这项工作尤其重要，因为它解决了FOS和JUN的功能，这是两个关键的药物成瘾调节剂。另外，通过鉴定活性调节的神经元蛋白，该程序可能会贡献成瘾的可塑性过程的新分子标记。最后，这些实验的结果可能会鉴定并验证新分子以靶向药理治疗。