Gsk3b in ethanol consumption and as a therapeutic target for alcohol use disorder

Gsk3b 在乙醇消耗中的作用以及作为酒精使用障碍的治疗靶点

• 批准号: 10647812
• 负责人: MICHAEL F MILES
• 金额: $ 34.93万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10647812
• 关键词: Acute; Address; Alcohol consumption; Alcohol withdrawal syndrome; Area; Behavior; Behavioral; Bioinformatics; Brain; Cells; Chronic; Clinical Research; Clinical Trials; Consumption; Corpus striatum structure; Cre-LoxP; Data; Disease; Dopamine D2 Receptor; Ethanol; Excision; Frequencies; GABA-A Receptor; Genes; Genetic; Genomics; Goals; Human; Immunohistochemistry; Knowledge; Learning; Lithium; LoxP-flanked allele; Manic; Medial; Mediating; Membrane; Messenger RNA; Molecular; Morphology; Mus; N-Methyl-D-Aspartate Receptors; Neurons; New Agents; Nucleus Accumbens; Organ; Pathway Analysis; Pattern; Phase II Clinical Trials; Phosphorylation; Phosphorylation Inhibition; Population; Potassium Channel; Prefrontal Cortex; Prevalence; Property; Prosencephalon; Regulation; Report (document); Rewards; Risk Factors; Rodent; Rodent Model; Role; Safety; Signal Transduction; Signaling Molecule; Site; Specificity; Synapses; Synaptic plasticity; Testing; Therapeutic Agents; Therapeutic Intervention; Therapeutic Uses; Time Study; Toxic effect; Viral Vector; Western Blotting; Work; alcohol abuse therapy; alcohol behavior; alcohol exposure; alcohol response; alcohol use disorder; anxiety-like behavior; autism spectrum disorder; behavioral sensitization; cell type; cocaine sensitization; conditional knockout; drinking; drinking behavior; drug of abuse; effectiveness evaluation; experimental study; gene network; gephyrin; glycogen synthase kinase 3 beta; glycogen synthase kinase 3 beta inhibitor; habituation; inhibitor; liver function; nervous system disorder; neural circuit; neuronal circuitry; novel; novel therapeutics; overexpression; pharmacologic; phase II trial; pre-clinical; pre-clinical assessment; preclinical evaluation; preclinical toxicity; receptor function; response; social anxiety; targeted treatment; therapeutic target; trafficking; transcriptome; transcriptome sequencing

This project studies the role of glycogen synthase kinase-3 beta (GSK3B) in modulation of ethanol consumption. GSK3B has been implicated as having an important role in synaptic plasticity and learning. Additionally, GSK3B has been suggested to modulate behaviors for other drugs of abuse. GSK3B has been shown by multiple studies to be inhibited by phosphorylation on residue Ser9 in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) of rodents after acute ethanol exposure. However, we recently found that prolonged ethanol consumption causes habituation of this inhibition of GSK3B by acute ethanol in PFC. Our recent studies on rodent drinking behavior show that pharmacological or genetic targeting inhibition of GSK3B in forebrain Camk2a+ neurons will decrease ethanol consumption. However, the mechanisms of GSK3B modulation of ethanol consumption are unknown. This proposal will perform a detailed analysis of ethanol regulation of GSK3B activity, and the specific cellular and neural circuits involved in GSK3B modulation of ethanol consumption. Aim 1 will investigate cellular sites of acute ethanol-induced GSK3B phosphorylation (inhibition) in mPFC and study the time course, duration and mechanisms of chronic ethanol-induced habituation of the acute response to ethanol. Viral vector and Cre-LoxP genetic targeting will be used in Aim 2 to identify whether Camk2a-positive neurons in mPFC are the critical site for GSK3B modulation of ethanol behaviors, and will identify downstream circuits of these neurons. RNAseq studies and bioinformatics in Aim 3 will then study genomic responses downstream of GSK3B following selective deletion or over-expression, thus identifying critical gene networks functioning in GSK3B modulation of ethanol consumption. Finally, Aim 4 will investigate the long-term efficacy and potential end-organ toxicity of Tideglusib, a highly specific inhibitor of GSK3B shown in preliminary studies to decrease ethanol consumption in rodent models. Tideglusib is already approved for phase II clinical trials on disorders such as autism. Together, these studies are highly significant and novel, and will provide needed knowledge regarding the mechanisms of GSK3B modulation of ethanol consumption. This work may also implicate a new agent, tideglusib, for clinical studies on treatment of AUD.

本课题研究了糖原合成酶-3β(GSK3B)在调节细胞周期中的作用。 乙醇消耗量。GSK3B被认为在突触中发挥重要作用 可塑性和学习。此外，GSK3B被建议用来调节 其他滥用药物。多项研究表明，GSK3B可被 内侧前额叶皮质和核中Ser9残基的磷酸化 急性酒精暴露对啮齿动物伏隔神经的影响。不过，我们最近发现， 长期饮酒可使急性酒精对GSK3B的抑制习惯化 在PFC里。我们最近对啮齿动物饮酒行为的研究表明，药理学或遗传学 靶向抑制前脑Camk2a+神经元中的GSK3B将减少乙醇消耗。 然而，GSK3B调节乙醇消耗的机制尚不清楚。这 提案将对乙醇对GSK3B活性的调节进行详细分析，并 参与GSK3B调节酒精消耗的特定细胞和神经回路。目标 1将研究急性乙醇诱导的GSK3B磷酸化(抑制)的细胞部位。 MPFC，并研究慢性乙醇诱导的时程、持续时间和机制 对乙醇的急性反应习惯化。病毒载体和Cre-loxP基因靶向 在目标2中用于确定mPFC中Camk2a阳性神经元是否是 GSK3B对乙醇行为的调制，并将识别这些神经元的下游电路。 然后，AIM 3中的RNAseq研究和生物信息学将研究下游的基因组反应 GSK3B在选择性缺失或过度表达后，从而识别关键基因网络 在GSK3B调节乙醇消耗中起作用。最后，目标4将调查 Tidelusib的长期疗效和潜在的终末器官毒性 初步研究表明，GSK3B可以减少啮齿动物模型的乙醇消耗。 替地卢西布已经被批准用于自闭症等疾病的第二阶段临床试验。一起， 这些研究具有非常重要的意义和新颖性，并将提供关于 GSK3B调节乙醇消耗的机制。这项工作还可能牵涉到一种新的 用于AUD临床研究的药物替地卢西布。