Gpr12: a novel factor for addiction and mental health

摘要 可卡因使用障碍药物治疗的发展滞后于药物治疗的发展 对其他精神疾病的治疗，如抑郁、焦虑或精神分裂症，在很大程度上是由于 缺乏新的治疗靶点。本项目是对题为“试点项目”的RFA-RM-18-021号文件的回应 研究未被充分研究的G蛋白偶联受体、离子通道和蛋白激酶。我们的目标， G蛋白偶联受体GPR12，PubMed评分13.55，PubTater评分8.24，符合条件 靶子是一个研究很少但可下药的靶子。作为对RFA的回应，本项目将使用我们的新型病毒 证实成瘾和/或抑郁相关的啮齿动物行为和电生理改变的载体 模特们。GPR12是通过核内基因表达的区域地形图差异来鉴定的 伏隔壳(ShNAc)作为创新的融合功能基因组学方法的一部分。该地区 表达分析与我们的可卡因和可卡因调节的转录数据集相结合 受环境丰富调控的转录，这是一种产生保护性成瘾的操作 表型。该项目的最终长期目标是开发一种有效的治疗可卡因的新方法。 成瘾或抑郁，这项特别拨款的近期目标是在 行为学和电生理学范式。这个项目的总体假设是，我们的汇聚 局部增强shNAc基因表达的功能基因组学方法(使用Allen脑 Atlas)与定量可卡因和环境浓缩RNA测序数据集相结合将 确定可开发用于治疗的新的可用药靶点。为了支持这一假设， ShNAc增强的蛋白质ATF3、Htr2c、Cartpt、Cyp26b1和Fabp5先前已经得到验证。目标1将 测试GPR12对大鼠可卡因摄取/寻找以及抑郁和焦虑模型的调节能力 这也严重依赖于shNAc。一种新型shRNA腺相关病毒载体将敲打 在行为测试前下调shNAc中GPR12的长期表达。以补充行为 实验，目标2将评估相应的神经元活性/兴奋性的功能变化 GPR12基因的敲除。目前为这一未被研究的靶点开发新疗法的障碍是 从以发现为基础的科学过渡到以假设为驱动的科学。目前的项目将通过以下方式克服这一障碍 为这一新的shNAc增强靶点的行为和电生理验证播种。

ABSTRACT The development of pharmacotherapeutics for cocaine use disorder has lagged behind development of therapies for other psychiatric conditions such as depression, anxiety or schizophrenia due in large part to a lack of novel therapeutic targets. The current project is in response to RFA-RM-18-021 entitled “Pilot Projects Investigating Understudied G Protein-Coupled Receptors, Ion Channels, and Protein Kinases”. Our target, the G-protein coupled receptor Gpr12, has a PubMed score of 13.55 and a PubTater score of 8.24, qualifying this target as a very understudied yet druggable target. In response to the RFA, this project will use our novel viral vector to validate addiction- and/or depression-related changes in rodent behavioral and electrophysiological models. Gpr12 was identified via regional topographical differences in gene expression in the nucleus accumbens shell (shNAc) as part of an innovative convergent functional genomics approach. The regional expression analysis is combined with our transcriptomic data set of transcripts regulated by cocaine and transcripts regulated by environmental enrichment, a manipulation that produces a protective addiction phenotype. The ultimate long-term goal of this project is to develop a useful novel therapeutic for cocaine addiction or depression, with the near-term objective of this specific grant being to validate this novel target in behavioral and electrophysiological paradigms. The overall hypothesis of this project is that our convergent functional genomics approach of regionally-enhanced gene expression in the shNAc (using the Allen Brain Atlas) combined with quantitative cocaine and environmental enrichment RNA-sequencing data sets will identify novel druggable targets that can be developed for therapeutic use. In support of this hypothesis, the shNAc-enhanced proteins Atf3, Htr2c, Cartpt, Cyp26b1, and Fabp5 have been validated previously. Aim 1 will test Gpr12 for its ability to regulate cocaine taking/seeking in rats, as well as depression and anxiety models that are also dependent heavily upon the shNAc. A novel shRNA adeno-associated viral vector will knock down long-term expression of Gpr12 in the shNAc prior to behavioral testing. To complement the behavioral experiments, Aim 2 will evaluate corresponding functional changes in neuronal activity/excitability after knockdown of Gpr12. The current barrier to developing novel therapeutics for this understudied target is the transition from discovery-based to hypothesis-driven science. The current project will overcome that barrier by seeding the behavioral and electrophysiological validation of this novel shNAc-enhanced target.