Circadian rhythms and alcohol in the BMAL1 knockout rat

BMAL1 敲除大鼠的昼夜节律和酒精

• 批准号: 10451307
• 负责人: SHANNON MARIE BAILEY
• 金额: $ 21.35万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10451307
• 关键词: ARNTL gene; Address; Alcohol consumption; Alcohol dependence; Alcoholic Liver Diseases; Alcohols; Animal Model; Animals; Bioenergetics; Biological Process; Brain Injuries; CRISPR/Cas technology; Cause of Death; Cell physiology; Cells; Chronotherapy; Circadian Dysregulation; Circadian Rhythms; Clinical; Complex; Depressed mood; Development; Disease; Dose; Ensure; Environmental Risk Factor; Ethanol toxicity; Etiology; Exhibits; Feedback; Fetal Alcohol Syndrome; Functional disorder; Gastrointestinal Diseases; Genes; Genetic; Genetic Transcription; Genotype; Goals; Health; Heart Diseases; Hepatic; Histopathology; Human; Immune System Diseases; Impairment; Inflammatory; Injury; Intestinal permeability; Kidney Diseases; Knock-out; Knowledge; Liver; Liver Mitochondria; Liver diseases; Malignant Neoplasms; Medical; Mental Health; Messenger RNA; Metabolic; Metabolism; Methods; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Molecular Target; Mus; Normal tissue morphology; Nutrient; Organ; Outcome; Outcomes Research; Output; Pathologic; Pathology; Pathway interactions; Patients; Physiological; Physiology; Production; Publishing; Rattus; Reactive Oxygen Species; Research; Research Personnel; Research Project Grants; Resolution; Respiration; Respiratory physiology; Rest; Risk; Risk Factors; Role; Stimulus; Stress; System; Technology; Testing; Time; Tissues; Transcript; Transcription Coactivator; Transcriptional Regulation; Ulcer; United States; Variant; Work; alcohol risk; base; chronic alcohol ingestion; circadian; circadian biology; clinically relevant; drug development; effective therapy; experimental study; genome editing; glycogen metabolism; high reward; knockout gene; lipid metabolism; liver function; liver injury; liver metabolism; metabolomics; molecular clock; novel; oxidative damage; pre-clinical; preclinical study; preventable death; problem drinker; respiratory; tissue injury; translational impact

PROJECT SUMMARY Liver disease is the number one cause of death from long-term heavy alcohol drinking in the United States. While dose and duration of alcohol consumption are well-accepted risk factors for disease, it is clear that the etiology of alcohol-related liver disease (ALD) is highly complex, involving many still unknown genetic, metabolic, and environmental factors. This complexity also likely explains why there are so few effective therapies for treating ALD. Therefore, a major unanswered question for the alcohol field is – what additional environmental factors, metabolic impairments, and/or molecular disturbances are required for liver pathology to occur in the alcohol consumer? A vital temporal integrator of environmental stimuli, metabolism, and cellular transcriptional control is the circadian system. At the cellular level, 24-h circadian rhythms are driven by a transcriptional-translational feedback loop system. This molecular clock mechanism involves activation of core clock genes and many downstream clock-output genes by the transcriptional activators BMAL1 and CLOCK. This molecular clock mechanism ensures that specific cellular and biological processes occur at the correct time of day. Accumulating evidence shows that circadian rhythm disruption worsens tissue function and injury in animals and humans consuming alcohol. Despite these new findings, the mechanistic understanding of how this occurs is very limited. This current proposal addresses a critical target of alcohol toxicity – the mitochondrion. Even though multiple studies have shown that alcohol severely impairs mitochondrial function, there have not been rigorous studies examining the impact of circadian disruption on temporal control of hepatic mitochondrial function in the alcohol consumer. We hypothesize that circadian disruption worsens alcohol-related impairments in hepatic mitochondrial bioenergetic function and increases tissue injury. To test this hypothesis, we will use an exciting new animal model, the Bmal1 knockout rat – the first rat model of a global clock gene knockout developed with CRISPR/Cas9 genome editing technology. In Aim 1, we will determine the role of Bmal1 in the temporal control of 24-h physiologic, metabolic, and molecular rhythms in alcohol-fed rats. In Aim 2, we will determine the role Bmal1 in alcohol-related mitochondrial bioenergetic dysfunction and liver injury. Successful completion of these studies will provide novel information regarding the interaction of the circadian system and alcohol on tissue and mitochondrial function and pathology. The knowledge gained from this work also has the ability to influence multiple scientific fields and facilitate development of novel chronotherapy-based approaches for treating patients suffering from ALD and other related liver diseases.

项目概要 在美国，肝病是长期大量饮酒导致死亡的第一大原因。尽管 饮酒的剂量和持续时间是公认的疾病危险因素，很明显，病因学 酒精相关性肝病 (ALD) 的发病机制非常复杂，涉及许多仍未知的遗传、代谢和 环境因素。这种复杂性也可能解释了为什么有效的治疗方法如此之少 酒精性肝病。因此，酒精领域一个尚未解答的主要问题是——还有哪些额外的环境因素， 酒精中发生肝脏病理需要代谢障碍和/或分子紊乱 消费者？环境刺激、新陈代谢和细胞转录控制的重要时间整合器 是昼夜节律系统。在细胞水平上，24小时昼夜节律是由转录翻译驱动的 反馈循环系统。这种分子时钟机制涉及核心时钟基因的激活和许多 转录激活子 BMAL1 和 CLOCK 控制下游时钟输出基因。这个分子钟 机制确保特定的细胞和生物过程在一天中的正确时间发生。积累中 有证据表明，昼夜节律紊乱会恶化动物和人类的组织功能和损伤 饮酒。尽管有这些新发现，但对这种现象如何发生的机制理解仍然非常有限。 目前的提案针对的是酒精毒性的一个关键目标——线粒体。即使多个 研究表明酒精严重损害线粒体功能，但尚未有严格的研究 研究昼夜节律紊乱对酒精中肝线粒体功能时间控制的影响 消费者。我们假设昼夜节律紊乱会加重酒精相关的肝损伤 线粒体生物能功能并增加组织损伤。为了检验这个假设，我们将使用一个令人兴奋的 新的动物模型，Bmal1 敲除大鼠——第一个全球时钟基因敲除的大鼠模型 CRISPR/Cas9基因组编辑技术。在目标 1 中，我们将确定 Bmal1 在时间控制中的作用 酒精喂养大鼠的 24 小时生理、代谢和分子节律。在目标 2 中，我们将确定角色 Bmal1 在酒精相关的线粒体生物能功能障碍和肝损伤中的作用。顺利完成这些 研究将提供有关昼夜节律系统和酒精对组织和细胞相互作用的新信息 线粒体功能和病理学。从这项工作中获得的知识也有能力影响 多个科学领域并促进开发基于时间疗法的新型患者治疗方法 患有ALD和其他相关肝脏疾病。