Fos, Jun &Transcriptional Control of Synaptic Plasticity

福斯，君

• 批准号: 6763438
• 负责人: MANI RAMASWAMI
• 金额: $ 9.8万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6763438
• 关键词: AP1 protein; Drosophilidae; JUN kinase; biological signal transduction; cAMP response element binding protein; cell morphology; double stranded RNA; gene mutation; genetic transcription; microarray technology; mitogen activated protein kinase; neural plasticity; neural transmission; neurogenetics; neuroregulation; phosphorylation; protein structure function; proteomics; serial analysis of gene expression; synapses; synaptogenesis; 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. The PI's 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. Exploiting the convenience of Drosophila as an experimental organism for rapid and incisive experiments on conserved biochemical pathways that underlie synapse plasticity, 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 AP1 and CREB-target genes proteins in neurons the program may help identify genes that confer predisposition to drug abuse or mood disorders in humans. Early AP1- response proteins may even provde to be new molecular markers of plasticity processes that underlie addiction. Finally, results from these experiments may identify and validate new molecules to targets for pharmacological therapy. The PI is an Associate Professor in a major undergraduate university with teaching and administrative commitments that limit the amount of effort the PI can contribute to research. These commitments are is particularly onerous at a stage when the PI is not only making substantial progress on current NIDA funded research, but also has an expanding program of promising and innovative research seeded in part by an NIDA CEBRA R21 grant. The PI is a relatively recent entry to the plasticity field and desires to bridge the gap between invertebrate and vertebrate work in neural plasticity addiction research. A K02 award would provide the PI additional time to: a) successfully perform funded research; b) stabilize a currently expanding program in plasticity research; and c) by interfacing with mammalian addiction researchers, help establish himself in the broad field of neural plasticity.

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的fosb，一种显性阴性的FOS同工型，会引起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。 PI最近的观察结果与意外的重要假设一致，即AP1在CREB上游。在已知可塑性相关的转录因子的层次结构的顶部。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。 提出的实验利用果蝇作为实验生物的便利性，以对持续的生物化学途径进行快速，敏锐的实验，这些实验是突触可塑性的基础，拟议的实验涉及突触重塑事件中基本重要性的领域，这些事件是行为变化的基础。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。此外，通过鉴定神经元中的AP1和CREB靶基因蛋白，该程序可能有助于鉴定人类赋予药物滥用或情绪障碍的基因。早期的AP1反应蛋白甚至可能是成瘾基础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的药理治疗靶标。 PI是一所主要本科大学的副教授，其教学和行政承诺限制了PI可以为研究做出贡献的努力。在PI不仅在当前的NIDA资助研究上取得了重大进展，而且还具有不断扩大的有前途和创新研究的计划，部分由NIDA CEBRA R21赠款播种。 PI是对可塑性领域的相对较新的进入，并且希望在神经可塑性成瘾研究中弥合无脊椎动物和脊椎动物工作之间的差距。 K02奖将为PI提供额外的时间：a）成功进行资助的研究； b）稳定当前扩展的可塑性研究计划； c）通过与哺乳动物成瘾的研究人员接触，帮助建立了自己的神经可塑性领域。