Elucidating alcohol-induced metabolic remodeling of critical organs

项目摘要/摘要 我们的目标是全面确定饮酒如何改变关键的代谢 器官，这可能会导致酒精引起的器官损伤。酒类消费是最主要的 造成全球公共卫生负担的原因。长期饮酒与 发展为肝硬变、肾功能不全、肠道炎症、免疫失调、 神经损伤和癌症。然而，人们仍然不完全了解酒精及其 代谢产物会影响器官新陈代谢，并可能导致器官损伤。新陈代谢是一个 动态的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并不提供有关代谢信息 活动。例如，血糖水平的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ALL的动态代谢活动 与酒精疾病有关的器官(目标1)。我们将采集动脉血和10个特定器官 酒精喂养受试者的静脉血，并使用液体- 色质联用(LC-MS)。这将告诉我们多少代谢物和哪种代谢物 被每个器官吸收或释放。在这项研究中，我们将使用猪，因为猪与 人类自愿饮酒行为、成瘾/醉酒表型和酒精 代谢率。通过测定~1,300种代谢物在猪体内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是如何通过 随着时间的推移饮酒。为了确定驱动酒精诱导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-seq，并使用新的生物信息学分析来 整合这两个组学数据(目标2)。生物信息学专家马库斯·塞尔丁博士随后将进行 使用他的创新计算工具进行系统的相关性分析。最后，我们会 使用功能获得/丧失验证培养细胞中最重要的候选基因-代谢物关系 实验。这些调节酒精诱导的器官代谢变化的基因可以是药物 旨在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 酒精在多个器官中的代谢变化以及关键负责基因，照亮了 预防酒精性器官代谢重塑的靶向治疗方法。

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.