PSYCHOTROPIC DRUG RESPONSIVE TRANSCRIPTION FACTORS

描述（申请人摘要）： 药物成瘾是美国主要的公共卫生问题之一 国家，并在很大程度上抗拒目前可用的预防和 治疗策略。 因此，近年来， 我对许多实验室，包括我自己的实验室， 细胞内信号通路，调节和介导的长期 神经元对各种生理和药理学的适应 刺激，包括滥用药物。 作为这一持续努力的一部分，我 申请更新我的K 02奖 这次续约能让我 我在分子生物学方法方面的进一步专业知识， 以前的研究。 本建议中概述的研究的具体目标侧重于 定义Egr家族的即时早期免疫调节的新方面， 基因转录因子 特别是，我们已经获得了证据， 初步研究表明，有明显的急性和延迟阶段， 由Egr反应元件介导的转录反应。 为 延迟阶段可能与理解长期 滥用药物对神经元功能的影响，我们计划进行 实验旨在：1）定义Egr家族成员， Egr家族表达“延迟”波，以及2）确定这两个 Egr家族成员表达的阶段受反复或慢性 刺激. 此外，在旨在确定 Egr家族成员在延迟期表达，我们获得了 这些证据之一，Egr-3，在体内被磷酸化。 尽管如此， 已知Egr家族成员如何受磷酸化调节，我们计划 3）绘制基础条件下Egr-3磷酸化位点的图谱， 第二信使途径激活后，和4）评估 磷酸化对其转录调节活性的影响。 获得进一步的专业知识，在分子生物学方法， 本提案中概述的研究将为以下方面奠定坚实的基础： 进行未来的研究，旨在确定信号通路， 调节神经可塑性和精神药物作用。 收盘 约翰斯大学神经科学系成员之间的互动 霍普金斯，其中包括领先的专家在分子神经生物学，提供 这是我科学发展的理想环境。

DESCRIPTION (Applicant's Abstract): Drug addiction is one of the major public health problems in the United states and is largely resistant to currently available prevention and treatment strategies. Accordingly, in recent years, there has been intense interest in numberous laboratories, including my own, in defining the intracellular signalling pthways that regulate and mediate the long-term adaptation of neurons to a wide variety of physiological and pharmacological stimuli, including drugs of abuse. As part of this ongoing effort, I am requesting renewal of my K02 award. This renewal will enable me to gain further expertise in molecular biological approaches I have employed in previous studies. The specific aims of the research outlined in this proposal focus on defining novel aspects of regulation of the Egr family of immediate early gene transcripiton factors. In particular, we have obtained evidence in preliminary studies that there are distinct acute and delayed phases to the transcriptional responses mediated by the Egr response element. As the delayed phase may be especially relevant to understanding the long-term effects of drugs of abuse on neuronal funciton, we plan to conduct experiments aimed at: 1) defining the Egr family members experessed durng the "delayed" wave of Egr family expression, and 2) determine how these two phases of Egr family member expression are influenced by repeated or chronic stimulation. In addition, in preliminary studies aimed at identifying the Egr family members expresed during the delayed phase, we have obtained evidence that one of these, Egr-3, is phosphorylated in vivo. As little is known about how Egr family members are regulated by phosphorylation, we plan to 3) map the sites of phosphorylation of Egr-3 under basal conditions and following activation of second messenger pathways, and 4) to assess the effects of phosphorylation on its transcriptional regulatory activity. Acquiring further expertise in molecular biological approaches by carrying out the studies outlined in this proposal will provide a firm foundation for pursuing future studies aimed at defining the signalling pathways that regulate neuronal plasticity and psychotropic drug actions. The close interaction among members of the Department of Neuroscience at Johns Hopkins, which include leading experts in molecular neurobiology, provides an ideal environment for my scientific development.