Targeting cell signaling pathways to disrupt drug abuse

项目摘要 药物滥用是一个巨大的公共卫生问题。因此，迫切需要改进我们的 了解药物滥用的分子机制，因为这一信息对开发 有效的策略来对抗这种疾病。因此，约翰霍普金斯药物滥用的总体目标 研究中心的目标是促进在确定介导药物作用的信号通路方面的进展， 虐待为了帮助实现这一目标，该中心将侧重于三个具体目标：1）促进协同 研究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，以及3）帮助培训药物滥用研究方面的领导人。 每个中心实验室将专注于创新的研究课题，将受益于协同 与其他实验室的互动。Worley实验室将研究mTORC 1激活的机制， 它在介导可卡因的强化特性中的作用。道森实验室将研究Thorase， AAA+ ATP酶家族，调节突触可塑性。特别是，最近的研究表明， 在调节mTORC 1信号复合物的分解中起关键作用。因此，这些研究高度 与Worley实验室的协同作用。巴拉班实验室将研究microRNA系统在 多巴胺信号他们发现，缺乏translin/trax RNA酶复合物的小鼠， 介导microRNA的一个子集的降解，在行为反应中产生强烈的改变， 可卡因斯奈德实验室将继续研究两项最新发现。其中一个项目将侧重于确定 Rheb/mTOR信号通路介导氯胺酮的行为效应，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方面发挥着重要作用 Rheb和Thorase，提供了另一个协同相互作用的节点。第二个项目是基于 意想不到的观察，可卡因，在纳摩尔浓度，触发自噬，一个过程密切相关， 与mTOR信号有关。由于可卡因在微摩尔范围内发挥其经典的行为效应， 研究结果表明，它还通过一种新的、高亲和力的“受体”影响细胞功能。斯奈德实验室将 在确定了可卡因的候选高亲和力“受体”的基础上，开展研究， 阐明其功能。 该中心将建立一个行为核心，在小鼠中进行自我给药试验。因为每个实验室 在小鼠中使用遗传操作来研究与可卡因作用相关的细胞信号传导途径， 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 可卡因的强化作用

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.