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: 10187469
• 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/10187469
• 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; 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; Pharmacology; Phase II Clinical Trials; Phosphorylation; Phosphorylation Inhibition; Population; Potassium; 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; base; behavioral sensitization; cell type; conditional knockout; drinking; drinking behavior; drug of abuse; effectiveness evaluation; experimental study; gamma-Aminobutyric Acid; gephyrin; glycogen synthase kinase 3 beta; glycogen synthase kinase 3 beta inhibitor; habituation; inhibitor/antagonist; liver function; nervous system disorder; neural circuit; novel; novel therapeutics; overexpression; 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.

本项目研究糖原合成酶激酶-3 β（GSK 3B）在调节 乙醇消费GSK 3B被认为在突触传导中具有重要作用。 可塑性和学习。此外，GSK 3B已被建议调节行为， 其他滥用药物。多项研究表明，GSK 3B被以下物质抑制： 内侧前额叶皮质（mPFC）和核中Ser 9残基的磷酸化 急性乙醇暴露后啮齿动物的NAc。然而，我们最近发现， 长期的乙醇消耗导致急性乙醇对GSK 3B的这种抑制的习惯化 我们最近对啮齿动物饮水行为的研究表明， 在前脑Camk 2a+神经元中靶向抑制GSK 3B将减少乙醇消耗。 然而，GSK 3B调节乙醇消耗的机制尚不清楚。这 该提案将对GSK 3B活性的乙醇调节进行详细分析， 参与GSK 3B调节乙醇消耗的特定细胞和神经回路。目的 1将研究急性乙醇诱导的GSK 3B磷酸化（抑制）的细胞位点， 研究慢性乙醇诱导的mPFC的时程、持续时间及机制 对乙醇的急性反应的习惯化。病毒载体和Cre-LoxP基因靶向将在 目的2中使用，以确定mPFC中的Camk 2a阳性神经元是否是 GSK 3B调节乙醇行为，并将确定这些神经元的下游回路。 目标3中的RNAseq研究和生物信息学将研究基因组下游的反应， 选择性缺失或过表达后的GSK 3B，从而鉴定关键基因网络 在GSK 3B调节乙醇消耗中起作用。最后，目标4将调查 Tideglusib的长期疗效和潜在的终末器官毒性，Tideglusib是一种高度特异性的 GSK 3B在初步研究中显示可减少啮齿动物模型中的乙醇消耗。 Tideglusib已经被批准用于自闭症等疾病的II期临床试验。在一起， 这些研究是非常重要和新颖的，并将提供所需的知识， GSK 3B调节乙醇消耗的机制。这项工作也可能涉及一个新的 用于治疗AUD的临床研究的药物替德格鲁西。