Alcohol dependence, epigenetic changes and sleep disruptions.

酒精依赖、表观遗传变化和睡眠中断。

基本信息

批准号：
8095108
负责人：
MAHESH M THAKKAR
金额：
$ 18.11万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-01 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8095108
关键词：
Abstinence Acetylation Acute Affect Alcohol consumption Alcohol dependence Alcohol withdrawal syndrome Alcoholic Beverages Alcoholism Alcohols Amygdaloid structure Anxiety Attenuated Bilateral Brain Chromatin Chronic Circadian Rhythms Clock protein Coupled DNA Sequence Rearrangement Disease Epigenetic Process Ethanol Exposure to FOS gene Gene Expression Histone Deacetylase Histone Deacetylase Inhibitor Histone H3 Histone H4 Human Intake Mediating Modeling Molecular Monitor Neurons Polysomnography Rattus Relapse Reporting Research Risk Risk Factors Role Sleep Sleep Disorders Sleep disturbances Sleeplessness Symptoms Synapses Testing Time Trichostatin A Wakefulness Withdrawal Withdrawal Symptom alcohol abuse therapy alcohol effect alcohol exposure alcoholism therapy basal forebrain base cholinergic drinking economic cost histone acetyltransferase non-alcoholic prevent problem drinker programs research study socioeconomics sound transcription factor treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Intake of alcoholic beverages has significant impact on sleep. Acute alcohol intake in non- alcoholics promotes sleepiness. In contrast, alcoholics, both during drinking period as well as during withdrawal suffer from profound and protracted insomnia and associated sleep disruptions that persist for several months during abstinence. Insomnia and associated sleep disturbances in recovering alcoholics are major risk factors for relapse to alcoholism. Thus, it is imperative that we understand and treat sleep disturbances in recovering alcoholics. The broad objective of this program of research is to elucidate the molecular mechanisms mediating the effects of ethanol on sleep-wakefulness and thereby provide a sound basis for the understanding and treatment of ethanol associated sleep disturbances and alcoholism. Our hypothesis: Profound insomnia and associated sleep disruptions observed during alcohol withdrawal are the result of epigenetic changes in the wake-promoting basal forebrain region. We predict that the expression of transcription factor, FosB/delta FosB will be increased in the wake-promoting basal forebrain region during ethanol withdrawal. We further predict that the expression of Clock protein, a key sleep and circadian regulator with histone acetyltransferase activity, will be reduced in the basal forebrain during ethanol withdrawal. Furthermore, we predict that chronic ethanol exposure will decrease acetylation of histones, H3 and H4, in the basal forebrain. Local and bilateral administration of histone deacetylase inhibitor, trichostatin-A, in the basal forebrain will attenuate chronic ethanol induced insomnia and associated sleep disruptions. PUBLIC HEALTH RELEVANCE: The broad objective of this research program is to understand the molecular mechanisms responsible for causing sleep disruptions during alcohol withdrawal and thereby provide a sound basis for the understanding and treatment of alcoholism.

描述（由申请人提供）：酒精饮料的摄入对睡眠有显着影响。非酗酒者的大量饮酒会导致嗜睡。相比之下，酗酒者在饮酒期间和戒断期间都会遭受严重且持久的失眠以及相关的睡眠中断，这种情况在戒酒期间持续数月。酗酒者康复过程中的失眠和相关睡眠障碍是酗酒复发的主要危险因素。因此，我们必须了解和治疗酗酒者康复过程中的睡眠障碍。该研究计划的广泛目标是阐明介导乙醇对睡眠觉醒影响的分子机制，从而为理解和治疗与乙醇相关的睡眠障碍和酒精中毒提供坚实的基础。我们的假设：戒酒期间观察到的严重失眠和相关的睡眠中断是促醒基底前脑区域表观遗传变化的结果。我们预测在乙醇戒断过程中，促进唤醒的基底前脑区域转录因子 FosB/delta FosB 的表达将会增加。我们进一步预测，在乙醇戒断期间，基底前脑中时钟蛋白（具有组蛋白乙酰转移酶活性的关键睡眠和昼夜节律调节剂）的表达将减少。此外，我们预测长期接触乙醇会降低基底前脑中组蛋白 H3 和 H4 的乙酰化。在基底前脑局部和双侧施用组蛋白脱乙酰酶抑制剂曲古抑菌素-A，将减轻慢性乙醇引起的失眠和相关的睡眠中断。公共卫生相关性：该研究计划的总体目标是了解戒酒期间导致睡眠中断的分子机制，从而为理解和治疗酒精中毒提供坚实的基础。