Gpr12: a novel factor for addiction and mental health

Gpr12：成瘾和心理健康的新因素

• 批准号: 9813292
• 负责人: Thomas Arthur Green
• 金额: $ 15.8万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9813292
• 关键词: Affect; Animal Model; Anxiety; Atlases; Behavior; Behavioral; Behavioral Paradigm; Brain; Brain region; Cells; Cocaine; Cocaine Dependence; Complement; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; DNA Methylation; Data; Data Set; Development; Disease; Disease model; Dopamine D1 Receptor; Electrophysiology (science); Ensure; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GPCR Signaling Pathway; GPR12 gene; Gene Expression; Genes; Genomic approach; Goals; Grant; Histones; Human Genome; Ion Channel Protein; Major Depressive Disorder; Manuscripts; Mediating; Mental Depression; Mental Health; MicroRNAs; Modeling; Nature; Neurons; Nucleus Accumbens; Pathway interactions; Phenotype; Pilot Projects; Preparation; Protein Kinase; Proteins; Proteome; PubMed; Qualifying; Rattus; Rodent; Role; Schizophrenia; Science; Seeds; Self Administration; Signal Transduction; Signaling Protein; Slice; Specificity; Sucrose; Synaptic Transmission; System; Testing; Therapeutic; Therapeutic Uses; Transcript; Validation; Viral Vector; Work; activating transcription factor 3; addiction; adeno-associated viral vector; base; behavior test; cocaine use; demethylation; druggable target; environmental enrichment for laboratory animals; experimental study; forced swim test; functional genomics; innovation; knock-down; new therapeutic target; novel; novel therapeutics; patch clamp; pre-clinical; preference; response; small hairpin RNA; therapeutic candidate; therapeutic development; therapeutic target; therapy development; tool; transcription factor; transcriptome sequencing; transcriptomics; vector

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.

摘要 可卡因使用障碍药物治疗的发展已经落后于药物治疗的发展。 治疗其他精神疾病，如抑郁症、焦虑症或精神分裂症， 缺乏新的治疗靶点。当前项目是对标题为“试点项目”的RFA-RM-18-021的响应 研究未充分研究的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Gpr 12的PubMed评分为13.55，PubTater评分为8.24，符合该标准。 作为一个尚未充分研究但可药用的目标。为了响应RFA，该项目将使用我们的新病毒 验证啮齿动物行为和电生理学中成瘾和/或抑郁相关变化的载体 模型通过细胞核中基因表达的区域地形差异来鉴定GPR 12。 作为创新的融合功能基因组学方法的一部分。区域 表达分析与我们的可卡因调节的转录物的转录组学数据集相结合， 受环境富集调节的转录物，这种操纵产生保护性成瘾 表型该项目的最终长期目标是开发一种有用的可卡因新疗法 成瘾或抑郁症，与此具体赠款的近期目标是验证这一新的目标， 行为和电生理学范例。这个项目的总体假设是， shNAc中区域增强基因表达的功能基因组学方法（使用艾伦脑 Atlas）结合定量可卡因和环境富集RNA测序数据集， 鉴定可开发用于治疗用途的新的可药用靶点。为了支持这一假设， shNAc增强的蛋白Atf 3、Htr 2c、Cartpt、Cyp 26 b1和Fabp 5先前已得到验证。目标1将 测试Gpr 12在大鼠以及抑郁和焦虑模型中调节可卡因服用/寻求的能力 也严重依赖于shNAc一种新的shRNA腺相关病毒载体将敲 在行为测试之前，降低shNAc中Gpr 12的长期表达。为了补充行为 实验中，目标2将评估神经元活性/兴奋性的相应功能变化， Gpr 12的敲除。目前，针对这一研究不足的靶点开发新疗法的障碍是， 从基于发现到基于假设的科学转变。目前的项目将克服这一障碍， 接种这种新的shNAc增强的靶标的行为和电生理学验证。