Casein Kinase 1, Alcohol Abuse and Comorbid Sleep and Circadian Disturbances

酪蛋白激酶 1、酗酒和共病睡眠和昼夜节律紊乱

• 批准号: 8683876
• 负责人: Stephanie Perreau-Lenz
• 金额: $ 26.76万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-05 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8683876
• 关键词: Affect; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohols; Behavior; Binding Sites; Biological Rhythm; Casein Kinase Iepsilon; Chronic; Circadian Rhythms; Clock protein; Corpus striatum structure; Development; Disease; Dose; Drug abuse; Enzymes; Evaluation; Functional disorder; Future; Gene Expression Regulation; Genes; Glycine; Goals; Health; Heart Diseases; Improve Access; Lead; Malignant Neoplasms; Mediating; Mental disorders; Modeling; Molecular; Molecular Target; Motor Activity; Mus; Mutant Strains Mice; Mutation; Pharmacologic Substance; Physiological; Pre-Clinical Model; Preventive; Protein Isoforms; Proteins; Protocols documentation; Rattus; Regulation; Relapse; Research; Risk; Role; Running; Self-Administered; Serine; Site; Sleep; Sleep Disorders; Sleep Fragmentations; Sleep Wake Cycle; Sleep disturbances; Societies; Susceptibility Gene; Testing; Therapeutic; Transgenic Organisms; Wakefulness; alcohol availability; alcohol craving; alcohol effect; alcohol exposure; alcohol relapse; alcohol seeking behavior; alcoholism therapy; base; binge drinking; casein kinase I; chronic alcohol ingestion; circadian pacemaker; drinking; drug abuse related behavior; drug development; improved; inhibitor/antagonist; insight; mouse model; neurobiological mechanism; novel; novel therapeutics; prevent; protective effect; sleep regulation; suprachiasmatic nucleus

DESCRIPTION (provided by applicant): Chronic alcohol abuse is associated with many physiological disturbances, resulting in numerous sleep disruptions, circadian desynchrony, and circadian clock gene dysregulation that may aggravate alcohol's negative effects and potentiate alcohol dependence. Circadian clock genes such as per2 are known to influence the development of alcohol abuse. Casein-kinase-1 epsilon and delta (CK1ε/δ), key post- translational players in the molecular circadian clock, regulates the availability of the clock protein PER2. CK1ε/δ have been implicated in sleep disorders as well as in drug abuse-related behaviors. I have recently shown that systemic administration of PF-670462, a CK1ε/δ inhibitor, prevents alcohol relapse-like drinking in chronic alcohol self-administering rats (Neuropsychopharmacology, 2012). The goal of the proposed research is to further test the beneficial effects of CK1ε/δ inhibition on alcohol abuse and comorbid sleep and circadian disturbances and provide insight into the neurobiological mechanisms involved. We will test whether the beneficial effect of CK1ε/δ inhibition observed on alcohol relapse can be replicated and affect other behaviors leading to alcohol dependence (e.g. alcohol binge-drinking). We hypothesize that (1) repeated alcohol binge-drinking episodes will affect the circadian period of locomotor activity and induce sleep disturbances, and (2) CK1ε/δ inhibition will decrease alcohol binge-drinking, restore the circadian period and ameliorate the disrupted effects on sleep. Based on our preliminary results, we further hypothesize that the protective effect of CK1ε/δ inhibition on alcohol consumption is mediated via the CK1δ isoform; and that CK1δ will affect alcohol binge drinking and subsequent circadian and sleep disturbances via the regulation of PER2 availability. In Year 1, we will test the hypothesis that CK1ε/δ inhibition will reduce alcohol binge drinking and normalize circadian function and sleep disruption in C57BL/6J mice. We will use a binge-drinking mouse protocol, called "drinking-in-the-dark" (DID), where multiple cycles of 4- days alcohol access followed by 2-bottle free choice alcohol access will occur over the course of weeks. We will additionally test if PF-670462 (1) dose-dependently reduces alcohol intake during binge drinking and subsequent free access to alcohol, (2) improves comorbid circadian dysfunction (e.g. free-running period and PER2 expression) and (3) ameliorates the expected sleep disturbances. In Year 2, we will use humanized hPER2S662G transgenic mutant mice to test whether a specific mutation of a CK1δ active binding site (S662) on the PER2 protein predisposes for alcohol binge-drinking. Alcohol intake, circadian function and sleep-wakefulness will be assessed using our established protocol. These results will provide insight into the role of CK1ε/δ in alcohol abuse, circadian rhythms and sleep mechanisms. Evaluation of the role of CK1ε/δ in the binge drinking model will help determine the utility of CK1ε/δ as a pharmaceutical target for the treatment of alcoholism.

描述（由适用提供）：慢性酒精滥用与许多身体疾病有关，导致无数的睡眠中断，昼夜节律降解和昼夜节律时钟基因失调，可能会加剧酒精的负面影响和潜在的酒精依赖性。众所周知，PER2等昼夜节律基因会影响酗酒的发展。酪蛋白 - 基因酶-1 Epsilon和Delta（CK1ε/δ），分子昼夜节律时钟中的关键转化后参与者，调节了时钟蛋白PER2的可用性。 CK1ε/δ已在睡眠障碍以及与药物滥用相关的行为中浸渍。我最近表明，CK1ε/δ抑制剂PF-670462的全身性给药可防止慢性酒精自我管理大鼠中酒精样饮酒（Neuropsyperopharmagology，2012年）。拟议的研究的目的是进一步测试CK1ε/δ抑制对酒精滥用和合并睡眠和昼夜节律疾病的有益作用，并提供对所涉及的神经生物学机制的见解。我们将测试是否可以重复观察到对酒精继电器观察到的CK1ε/δ抑制作用的有益作用，并影响导致酒精依赖性的其他行为（例如，酒精暴饮暴食）。我们假设（1）反复的酒精暴饮暴食会影响运动活性的昼夜节律时期并诱导睡眠障碍，并且（2）CK1ε/δ抑制作用会减少酒精暴饮暴食，恢复昼夜节律并降低对睡眠的残疾人的影响。基于我们的初步结果，我们进一步假设CK1ε/δ抑制对酒精消耗的保护作用是通过CK1δ同工型介导的。 CK1δ会通过调节PER2的可用性来影响酒精暴饮暴食和随后的昼夜节律。在第1年，我们将检验以下假设：CK1ε/δ抑制作用将减少酒精饮料饮酒，并在C57BL/6J小鼠中使昼夜节律归一化和睡眠破坏。我们将使用一种暴饮暴食的小鼠协议，称为“黑暗中饮用”（DID），其中4天酒精获取的多个周期将在数周的过程中发生，然后进行2瓶免费的酒精醇醇进入。还将测试PF-670462（1）剂量依赖性地降低酒精饮酒期间的酒精摄入量，并随后自由饮酒，（2）改善了合并症的昼夜节律功能障碍（例如，自由运行时期和PER2表达）和（3）降低了预期的睡眠障碍。在第二年，我们将使用人源化的HPER2S662G转基因突变小鼠测试CK1Δ活性结合位点（S662）的特异性突变是否在PER2蛋白易于饮用的PER2蛋白上。酒精摄入量，昼夜节律功能和睡眠能力将使用我们既定的方案进行评估。这些结果将洞悉CK1ε/δ在酒精滥用，昼夜节律和睡眠机制中的作用。评估CK1ε/δ在暴饮暴食模型中的作用将有助于确定CK1ε/δ作为治疗酒精中毒的药物的实用性。