Targeting cell signaling pathways to disrupt drug abuse

项目概要 药物滥用是一个巨大的公共卫生问题。因此，我们迫切需要改进 了解药物滥用的分子机制，因为这些信息对于发展至关重要 对抗这种疾病的有效策略。因此，约翰·霍普金斯大学药物滥用研究的总体目标 研究中心将促进在定义介导药物作用的信号通路方面取得进展 滥用。为了帮助实现这一目标，该中心将重点关注三个具体目标：1）促进协同作用 调查药物滥用分子作用的中心实验室之间的相互作用，2) 鼓励 在这一领域应用创新方法，3) 帮助培训药物滥用研究领域的领导者。 每个中心实验室都将重点关注将从协同作用中受益的创新研究主题 与其他中心实验室的互动。 Worley 实验室将研究 mTORC1 激活机制并 它在调节可卡因的增强特性中的作用。道森实验室将研究索拉斯（Thorase），他是 AAA ATP酶家族，调节突触可塑性。特别是，最近的研究表明，Thorase 扮演 在调节 mTORC1 信号复合物的分解中发挥关键作用。因此，这些研究具有很高的 与沃利实验室的协同作用。 Baraban 实验室将研究 microRNA 系统在 多巴胺信号传导。他们发现小鼠缺乏易位蛋白/trax RNase 复合物，这是一种关键酶， 介导一部分 microRNA 的降解，对行为反应产生强烈的改变 可卡因。斯奈德实验室将继续研究最近的两项发现。一个项目将侧重于定义 Rheb/mTOR 信号通路介导氯胺酮行为效应，与研究直接相关 由沃利和道森实验室进行。此外，亚硝基化在调节两者中起着重要作用 Rheb 和 Thorase，提供了另一个协同相互作用的节点。第二个项目基于 意想不到的观察发现，纳摩尔浓度的可卡因会引发自噬，这是一个密切相关的过程 与 mTOR 信号传导有关。由于可卡因在微摩尔范围内发挥其经典的行为效应，这些 研究结果表明，它还通过一种新型的高亲和力“受体”影响细胞功能。斯奈德实验室将 基于对可卡因候选高亲和力“受体”的鉴定，开展旨在 阐明其功能。 该中心将建立一个行为核心来对小鼠进行自我给药测定。由于各个实验室 使用小鼠基因操作来研究与可卡因作用相关的细胞信号传导途径，行为 核心将是一个完整的、共享的设施，对于评估操纵这些途径对人类的影响至关重要。 可卡因的强化特性。

Project Summary Drug abuse is an enormous public health problem. Accordingly, there is an urgent need to improve our understanding of the molecular mechanisms underlying drug abuse, as this information is vital to developing effective strategies to combat this disorder. Therefore, the overall goal of the Johns Hopkins Drug Abuse Research Center is to catalyze progress in defining the signaling pathways that mediate actions of drugs of abuse. To help achieve this goal, the Center will focus on three specific aims: 1) to catalyze synergistic interactions among Center laboratories investigating molecular actions of drug abuse, 2) to encourage application of innovative approaches to this field, and 3) to help train leaders in drug abuse research. Each of the Center laboratories will focus on innovative topics of research that will benefit from synergistic interactions with other Center laboratories. The Worley lab will study mechanisms of mTORC1 activation and its role in mediating the reinforcing properties of cocaine. The Dawson lab will study Thorase, a member of the AAA+ ATPase family, that regulates synaptic plasticity. In particular, recent studies indicate that Thorase plays a key role in regulating disassembly of mTORC1 signaling complexes. Thus, these studies are highly synergistic with those of the Worley lab. The Baraban lab will study the role of the microRNA system in dopamine signaling. They have found that mice lacking the translin/trax RNase complex, a key enzyme that mediates degradation of a subset of microRNAs, produces robust alterations in behavioral responses to cocaine. The Snyder lab will pursue two recent discoveries. One project will focus on defining the role of the Rheb/mTOR signaling pathway in mediating behavioral effects of ketamine, which links directly to studies conducted by the Worley and Dawson labs. Furthermore, nitrosylation plays a major role in regulating both Rheb and Thorase, providing another node of synergistic interaction. The second project is based on the unexpected observation that cocaine, at nanomolar concentrations, triggers autophagy, a process intimately linked to mTOR signaling. As cocaine exerts its classic behavioral effects in the micromolar range, these findings suggest that it also affects cellular function via a novel, high affinity “receptor”. The Snyder lab will build on its identification of a candidate high affinity “receptor” for cocaine to pursue studies aimed at elucidating its function. The Center will establish a Behavioral Core to conduct self-administration assays in mice. As each laboratory uses genetic manipulations in mice to study cell signaling pathways relevant to cocaine action, the Behavioral Core will be an integral, shared facility critical for evaluating the impact of manipulating these pathways on cocaine's reinforcing properties.