Circadian and mitochondrial dysfunction in alcohol-related liver disease

酒精相关性肝病中的昼夜节律和线粒体功能障碍

基本信息

批准号：
10667861
负责人：
SHANNON MARIE BAILEY
金额：
$ 51.86万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-10 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10667861
关键词：
ARNTL gene Acceleration Affect Alcohol Hepatotoxicity Alcohol consumption Alcohol-Induced Disorders Alcoholic Liver Diseases Alcohols Area Automobile Driving Bioenergetics Biological Biological Pacemakers Cause of Death Chronic Chronobiology Circadian Dysregulation Circadian Rhythms Clinical Complex Consumption DNA Sequence Alteration Data Diet Disease Diurnal Rhythm Doxycycline E4BP4 Environmental Risk Factor Enzymes Exhibits Functional disorder Generations Genes Genetic Genetic Transcription Genotype Goals Health Hepatic Hepatocyte Histopathology Hydrogen Peroxide Impairment Injury Knock-out Knowledge Liver Liver Mitochondria Liver diseases Maintenance Measures Metabolic dysfunction Methods Mitochondria Mitochondrial DNA Modeling Molecular Mus Organ Outcomes Research Output Oxidation-Reduction Pathogenesis Pathologic Pathology Patients Periodicity Physiological Play Proteome Proteomics Reactive Oxygen Species Research Project Grants Resolution Respiration Role Serum Site Spirometry Stimulus Stress System Testing Tetanus Helper Peptide Therapeutic Triglycerides United States Variant alcohol prevention chronic alcohol ingestion circadian circadian pacemaker comparison control complex IV cytochrome c oxidase deter alcohol use drug development drug discovery effective therapy enzyme activity extracellular fatty acid oxidation glucose metabolism glycogen metabolism improved insight lipidome liver injury mitochondrial dysfunction mitochondrial metabolism mouse model nicotinamide-beta-riboside novel strategies novel therapeutics pharmacologic pre-clinical prevent preventable death respiratory small molecule tissue repair translational impact

项目摘要

PROJECT SUMMARY Alcohol-related liver disease (ALD) is the number one cause of death from long-term and excessive alcohol use in the United States. One early and primary target of alcohol hepatotoxicity is the mitochondrion. Chronic alcohol consumption severely compromises liver mitochondrial bioenergetic function; however, the specific molecular mechanisms responsible for mitochondrial damage are not well understood. We also do not know the full contribution of mitochondrial dysfunction in pathobiology of ALD. Accumulating evidence supports the concept that an intrinsic biological mechanism known as the molecular circadian clock regulates how organs respond to external environmental factors, as well as internal physiological stimuli and abnormal pathologic stresses. There is a growing body of evidence that circadian rhythms are disrupted by chronic alcohol use, which likely contribute to disease as genetic mutation or deletion of clock genes increase metabolic dysfunction and liver pathology in alcohol models. Regarding this scientific premise, we discovered that chronic alcohol significantly deceases liver clock amplitude and disrupts the timing of the liver clock. Alcohol-fed mice with liver-specific deletion of Bmal1 exhibit impaired glucose and glycogen metabolism rhythms, a dysregulated hepatic triglyceride lipidome, and a greater liver disease pathology score compared to control genotype mice fed an alcohol diet. We also have exciting new preliminary data showing chronic alcohol significantly dampens and disrupts rhythmicity of critical hepatic mitochondrial bioenergetic functions, including activity of cytochrome c oxidase, the rate-limiting enzyme of mitochondrial respiration. Building on these exciting new observations, we offer a new paradigm where loss in circadian control of mitochondrial bioenergetic function during chronic alcohol consumption plays a key causal role in the pathogenesis of ALD. We will test this hypothesis through three Specific Aims. In Aim 1, we will establish that chronic alcohol consumption disrupts 24-h rhythms in hepatic mitochondrial bioenergetic function. In Aim 2, we will define the roles of hepatocyte BMAL1 and E4BP4 in alcohol-induced mitochondrial bioenergetic dysfunction and liver injury. In Aim 3, we will test if reinstating liver clock activity during alcohol use prevents mitochondrial dysfunction and liver injury. These results will provide the first insights into the relationship between the circadian system and alcohol on mitochondrial bioenergetics and organ damage. Project findings will have direct translational impact by advancing pre-clinical scientific knowledge required for stimulating drug discovery in the areas of mitochondrial and chronobiology based therapeutics for treating patients afflicted with ALD and other serious liver diseases.

项目摘要与酒精有关的肝病（ALD）是长期和过度使用酒精的死亡原因第一在美国。酒精肝毒性的一个早期和主要靶标是线粒体。慢性酒精消费严重损害了肝线粒体生物能功能；但是，特定的分子对线粒体损伤负责的机制尚不清楚。我们也不知道线粒体功能障碍在ALD病理生物学中的贡献。积累证据支持该概念一种固有的生物学机制称为分子昼夜节律时钟，调节器官如何反应外部环境因素以及内部生理刺激和异常的病理应激。那里是越来越多的证据表明昼夜节律饮酒会破坏昼夜节律，这可能有助于作为遗传突变或时钟基因缺失的疾病会增加代谢功能障碍和肝病病理学酒精模型。关于这个科学的前提，我们发现慢性酒精显着脱离肝脏时钟振幅并破坏肝时钟的时间。 BMAL1的酒精喂养小鼠具有肝脏特异性缺失表现出受损的葡萄糖和糖原代谢节奏，肝甘油三酸酯脂肪组的失调，A 与喂养酒精饮食的对照基因型小鼠相比，肝病病理学的得分更高。我们也有令人兴奋肝线粒体生物能功能，包括细胞色素C氧化酶的活性，速率限制酶线粒体呼吸。在这些令人兴奋的新观察基础上，我们提供了一个新的范式，损失在昼夜节日控制慢性酒精期间线粒体生物能功能的控制中在ALD的发病机理中的作用。我们将通过三个特定目标检验这一假设。在AIM 1中，我们将确定慢性酒精消耗会破坏肝线粒体生物能功能中的24小时节奏。在AIM 2中，我们将定义肝细胞BMAL1和E4BP4在酒精诱导的线粒体生物核中的作用功能障碍和肝损伤。在AIM 3中，我们将测试在饮酒期间恢复肝时钟活动是否防止线粒体功能障碍和肝损伤。这些结果将为您提供有关之间关系的第一个见解线粒体生物能和器官损伤的昼夜节律系统和酒精。项目发现将有通过促进刺激药物发现所需的临床前科学知识来直接翻译影响在基于线粒体和计时生物学的领域，用于治疗患有ALD和ALD的患者其他严重的肝病。