Elucidating alcohol-induced metabolic remodeling of critical organs

阐明酒精诱导的关键器官代谢重塑

• 批准号: 10667050
• 负责人: Cholsoon Jang
• 金额: $ 41.21万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-12 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667050
• 关键词: Acetaldehyde; Adipose tissue; Affect; Alcohol consumption; Alcoholic Liver Cirrhosis; Alcoholic steatohepatitis; Alcohols; Anatomy; Animal Model; Attention; Bioinformatics; Blood; Blood Glucose; Blood alcohol level measurement; Candidate Disease Gene; Catabolism; Circadian Rhythms; Cirrhosis; Consumption; Cultured Cells; DNA Damage; Data; Data Analyses; Development; Diet; Disease; Drug Targeting; Enzymes; Epigenetic Process; Ethanol Metabolism; Exhibits; Family suidae; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Foundations; Functional disorder; Gene Expression; Genes; Genetic; Goals; Harvest; Heavy Drinking; Hepatic; Human; Human Cell Line; Immune; Individual; Inflammation; Intoxication; Link; Lipids; Liver; Machine Learning; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Mediating; Metabolic; Metabolism; Methods; Modification; Movement; Nervous System Trauma; Organ; Organism; Pathologic; Phenotype; Process; Production; Proteins; Protocols documentation; Public Health; Rodent; Role; Surveys; Systemic disease; Time; Tissues; Validation; Venous; absorption; addiction; alcohol effect; alcohol prevention; binge drinking; chronic alcohol ingestion; computerized tools; disability-adjusted life years; disease diagnosis; drinking behavior; experimental study; feeding; gene discovery; gene product; gut inflammation; innovation; insight; kidney dysfunction; knock-down; liquid chromatography mass spectrometry; loss of function; metabolic rate; metabolomics; motor deficit; overexpression; porcine model; problem drinker; trafficking; transcriptome sequencing; translational potential; validation studies

Project Summary/Abstract We aim to comprehensively determine how alcohol consumption alters the metabolism of critical organs, which can contribute to alcohol-induced organ damage. Alcohol consumption is the leading cause of public health burden worldwide. Chronic alcohol consumption is tightly associated with the development of cirrhosis, kidney dysfunction, intestinal inflammation, immune dysregulation, neurological damage, and cancers. However, it is still incompletely understood how alcohol and its metabolic products impact organ metabolism and potentially cause organ damage. Metabolism is a dynamic process like a flowing river. However, conventional methods that measure static snapshots such as gene expression, protein, or metabolite levels do not provide information about metabolic activities. For example, increased blood glucose levels can be due to either elevated production or reduced consumption by a dozen of organs. To resolve this issue, we will employ our unique platform, arteriovenous (AV) metabolomics, to quantitatively measure the dynamic metabolic activities of all organs relevant to alcoholic diseases (Aim 1). We will collect arterial blood and 10 organ-specific venous blood from alcohol-fed subjects and measure metabolite concentration gradients using liquid- chromatography mass spectrometry (LC-MS). This will inform how much and what kind of metabolites are absorbed or released by each organ. For this study, we will use pigs because pigs are similar to humans in terms of voluntary alcohol drinking behavior, addiction/intoxication phenotypes, and alcohol metabolic rate. By measuring ~1,300 metabolites’ movements between 10 major organs in pigs after alcohol feeding for three different durations, we will elucidate how each organ’s metabolism changes by alcohol consumption over time. To identify genes that drive alcohol-induced organ metabolic changes, we will also perform RNA-seq in the same pig tissues and employ new bioinformatics analysis to integrate these two omics data (Aim 2). Dr. Marcus Seldin, a bioinformatics expert, will then perform a battery of systematic correlation analyses using his innovative computational tools. Finally, we will validate the top candidate gene-metabolite relationships in cultured cells using gain/loss-of-function experiments. Such genes that mediate the alcohol-induced organ metabolism changes can be drug targets to mitigate alcohol’s detrimental effects. Our study will thus delineate previously unrecognized metabolic changes by alcohol in multiple organs as well as the key responsible genes, illuminating the way for targetable therapy to prevent alcohol-induced organ metabolic remodeling.

项目概要/摘要 我们的目标是全面确定饮酒如何改变关键的新陈代谢 器官，这可能导致酒精引起的器官损伤。酒精消费占主导地位 造成全世界公共卫生负担的原因。长期饮酒与饮酒密切相关 肝硬化、肾功能障碍、肠道炎症、免疫失调的发展， 神经损伤和癌症。然而，人们仍然不完全了解酒精及其作用如何 代谢产物影响器官代谢并可能导致器官损伤。新陈代谢是一个 动态过程就像一条流动的河流。然而，测量静态快照的传统方法 例如基因表达、蛋白质或代谢物水平不提供有关代谢的信息 活动。例如，血糖水平升高可能是由于产量增加或 减少了十几个器官的消耗。为了解决这个问题，我们将利用我们独特的平台， 动静脉（AV）代谢组学，定量测量所有动静脉的动态代谢活动 与酒精疾病相关的器官（目标 1）。我们将收集动脉血和10个器官特异性 来自饮酒受试者的静脉血，并使用液体测量代谢物浓度梯度 色谱质谱法（LC-MS）。这将告知代谢物的数量和种类 被各个器官吸收或释放。在本研究中，我们将使用猪，因为猪与 人类自愿饮酒行为、成瘾/中毒表型和酒精 代谢率。通过测量约 1,300 种代谢物在猪的 10 个主要器官之间的移动 酒精喂养三个不同的持续时间，我们将通过以下方式阐明每个器官的新陈代谢如何变化 随着时间的推移饮酒量。为了识别驱动酒精引起的器官代谢变化的基因， 我们还将在相同的猪组织中进行 RNA 测序，并采用新的生物信息学分析来 整合这两个组学数据（目标 2）。生物信息学专家 Marcus Seldin 博士随后将进行 使用他的创新计算工具进行一系列系统相关分析。最后，我们将 使用功能获得/丧失来验证培养细胞中最重要的候选基因-代谢物关系 实验。这种介导酒精引起的器官代谢变化的基因可以作为药物 减轻酒精有害影响的目标。因此，我们的研究将描绘出以前未被认识到的 酒精对多个器官以及关键负责基因的代谢变化，阐明了 靶向治疗预防酒精引起的器官代谢重塑的方法。