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

基本信息

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
项目类别：
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

项目摘要

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.

该项目研究糖原合酶激酶 3 beta (GSK3B) 在调节中的作用乙醇消耗。 GSK3B 被认为在突触中具有重要作用可塑性和学习性。此外，GSK3B 已被建议调节行为其他滥用药物。多项研究表明 GSK3B 会被抑制内侧前额皮质 (mPFC) 和细胞核中残基 Ser9 的磷酸化急性乙醇暴露后啮齿动物的伏隔核（NAc）。然而，我们最近发现长时间的乙醇消耗导致对急性乙醇对 GSK3B 的抑制的习惯在 PFC 中。我们最近对啮齿动物饮酒行为的研究表明，药理学或遗传因素靶向抑制前脑 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。这该提案将对乙醇对 GSK3B 活性的调节进行详细分析，参与 GSK3B 乙醇消耗调节的特定细胞和神经回路。目的 1 将研究急性乙醇诱导的 GSK3B 磷酸化（抑制）的细胞位点 mPFC 并研究慢性乙醇诱发的时程、持续时间和机制习惯对乙醇的急性反应。病毒载体和 Cre-LoxP 基因靶向将用于目标 2，以确定 mPFC 中的 Camk2a 阳性神经元是否是 GSK3B 调节乙醇行为，并将识别这些神经元的下游回路。 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 选择性删除或过度表达，从而识别关键基因网络在 GSK3B 乙醇消耗调节中发挥作用。最后，目标 4 将调查 Tideglusib 的长期疗效和潜在的终末器官毒性，一种高度特异性的抑制剂初步研究显示 GSK3B 可以减少啮齿动物模型中的乙醇消耗。 Tideglusib 已被批准进行针对自闭症等疾病的 II 期临床试验。一起，这些研究非常重要且新颖，并将提供有关 GSK3B 调节乙醇消耗的机制。这项工作还可能涉及一个新的药物，tideglusib，用于治疗 AUD 的临床研究。