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.

项目摘要/摘要 我们旨在全面确定饮酒如何改变关键的代谢 器官，可能导致酒精引起的器官损伤。饮酒是领先的 全球公共卫生伯恩的原因。长期饮酒与 肝硬化，肾功能障碍，肠炎，免疫失调， 神经损害和癌症。但是，它仍然不完全理解酒精及其如何 代谢产物会影响器官代谢，并可能导致器官损伤。代谢是一个 像流动的河流一样的动态过程。但是，测量静态快照的常规方法 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升高或 减少了十几个器官的消费。为了解决这个问题，我们将采用我们独特的平台 动静脉（AV）代谢组学，以定量测量所有人的动态代谢活性 与酒精性疾病有关的器官（AIM 1）。我们将收集动脉血和10个器官特异性 来自酒精喂养受试者的静脉血，并使用液体测量代谢物浓度梯度 色谱质谱法（LC-MS）。这将告知多少代谢物 每个器官都吸收或释放。对于这项研究，我们将使用猪，因为猪与 人类在自愿饮酒行为，成瘾/中毒表型和酒精方面 代谢率。通过测量约1,300个代谢物在猪中的10个主要器官之间的运动 酒精喂养三个不同的持续时间，我们将阐明每个器官的新陈代谢如何通过 随着时间的流逝，饮酒。确定驱动酒精诱导器官代谢变化的基因， 我们还将在同一猪组织中进行RNA-Seq，并将员工进行新的生物信息学分析至 集成了这两个OMIC数据（AIM 2）。生物信息学专家Marcus Seldin博士然后将执行 使用其创新的计算工具进行系统的系统相关分析。最后，我们会的 使用功能丧失/功能丧失来验证培养细胞中顶级候选基因代谢物的关系 实验。介导酒精诱导的器官代谢变化的基因可能是药物 因此，我们的研究将描绘以前未被认可的 多个器官和关键负责基因的饮酒代谢变化，阐明了 可预防酒精诱导器官代谢重塑的靶向疗法的方法。