Mouse Models and Metabolomics Tools to Investigate Alcohol Metabolism and Tissue Injury

研究酒精代谢和组织损伤的小鼠模型和代谢组学工具

基本信息

批准号：
10474322
负责人：
VASILIS VASILIOU
金额：
$ 51.12万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10474322
关键词：
Abbreviations Acetaldehyde Acute Affect Alcohol abuse Alcohol consumption Alcohol dehydrogenase Alcohol dependence Alcohols Aldehydes Animal Model Antioxidants Biochemical Biochemical Pathway Bioinformatics Biological Process CYP2E1 gene Cancer Model Capital Catalytic Domain Cells Collaborations Colon Carcinoma Communities Consultations Cytochrome P450 DNA Detection Development Disease Enzymes Ethanol Ethanol Metabolism Ethanol toxicity Experimental Designs Felis catus GCLC gene GCLM gene Genes Genetic Polymorphism Glutamate-Cysteine Ligase Glutathione Goals Hepatocyte In Situ Intention Investigation Italy Knock-out Knockout Mice Knowledge Letters Lipids LoxP-flanked allele Malignant Neoplasms Mammals Maps Mediating Messenger RNA Metabolic Methodology Mitochondria Modeling Molecular Molecular Weight Mus Mutagenesis Mutation National Institute on Alcohol Abuse and Alcoholism Nitrogen Oxidative Stress Oxygen Pathogenesis Play Population Predisposition Process Proteins Reactive Nitrogen Species Reactive Oxygen Species Research Research Personnel Resources Role Sampling System Techniques Tissue imaging Tissues Toxic effect Transgenic Animals Transgenic Mice Transgenic Organisms adduct alcohol abuse therapy alcohol consequences alcohol effect alcohol exposure aldehyde dehydrogenases catalase cell injury chronic alcohol ingestion conditional knockout effective therapy gene product insight knockout gene mass spectrometric imaging metabolomics metabolomics resource mouse model mutant nuclear factor-erythroid 2 small molecule symposium tissue injury tool

项目摘要

ABSTRACT The deleterious effects of alcohol are primarily mediated by its metabolic by-products. Ethanol metabolism by microsomal and mitochondrial systems generates reactive oxygen and nitrogen species, and is associated with diminished glutathione and antioxidant enzymatic activity, all of which promote oxidative stress. In addition, the accumulation of ethanol-derived aldehydes and hydroxyethyl radicals serves to modify critical biological functions by forming adducts with proteins and DNA. The availability of animal models in which ethanol metabolism or antioxidant mechanisms are genetically modified facilitates investigation of the role these enzymes and oxidative stress play in diseases associated with ethanol consumption. The goals of this application are to: A) maintain and develop unique transgenic knockouts that can be made available to the larger research community for the investigation of the pathogenesis of alcohol abuse and the mechanisms underlying the deleterious effects of alcohol, and B) offer metabolomics and tissue imaging mass spectrometry (IMS) expertise to facilitate investigation of the biochemical consequences of alcohol exposure and pathogenesis. Our overarching aim is to provide valuable transgenic animal models and metabolomics resources to the larger research community that will greatly enhance our understanding of the mechanisms underlying alcohol-induced disease and the pathophysiological effects of acute and chronic alcohol consumption. It is anticipated that our metabolomic platforms will offer state-of-the-art techniques to dissect the molecular mechanisms of alcohol-induced tissue injury. Such knowledge will facilitate the development of more effective treatments of alcohol abuse.

抽象的酒精的有害作用主要是由其代谢副产物介导的。微粒体的乙醇代谢线粒体系统产生活性氧和氮，并与谷胱甘肽减少有关和抗氧化酶活性，所有这些都会促进氧化应激。此外，乙醇衍生的积累醛和羟乙基自由基通过与蛋白质和 DNA 形成加合物来改变关键的生物功能。乙醇代谢或抗氧化机制经过基因改造的动物模型的可用性有助于研究这些酶和氧化应激在与乙醇消耗相关的疾病中所起的作用。这该应用的目标是：A) 维持和开发独特的转基因敲除技术，可供更大的研究团体致力于调查酒精滥用的发病机制及其背后的机制酒精的有害影响，B) 提供代谢组学和组织成像质谱 (IMS) 专业知识，以促进研究酒精暴露的生化后果和发病机制。我们的首要目标是提供为更大的研究界提供宝贵的转基因动物模型和代谢组学资源，这将大大增强我们对酒精诱发疾病的机制以及急性和慢性酒精中毒的病理生理学影响的理解长期饮酒。预计我们的代谢组学平台将提供最先进的技术来剖析酒精引起的组织损伤的分子机制。这些知识将有助于开发更有效的酗酒的治疗。

项目成果

期刊论文数量（29）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

ALDH1B1 Is Crucial for Colon Tumorigenesis by Modulating Wnt/β-Catenin, Notch and PI3K/Akt Signaling Pathways.

ALDH1B1 通过调节 Wnt/β-Catenin、Notch 和 PI3K/Akt 信号通路对结肠肿瘤发生至关重要。

DOI：
发表时间：
2015
期刊：
影响因子：
3.7
作者：
Singh, Surendra;Arcaroli, John;Chen, Ying;Thompson, David C;Messersmith, Wells;Jimeno, Antonio;Vasiliou, Vasilis
通讯作者：
Vasiliou, Vasilis

Integrated multi-omics approach reveals a role of ALDH1A1 in lipid metabolism in human colon cancer cells.

综合多组学方法揭示了 ALDH1A1 在人类结肠癌细胞脂质代谢中的作用。

DOI：
10.1016/j.cbi.2019.02.030
发表时间：
2019-05-01
期刊：
Chemico-biological interactions
影响因子：
5.1
作者：
Charkoftaki G;Thompson DC;Golla JP;Garcia-Milian R;Lam TT;Engel J;Vasiliou V
通讯作者：
Vasiliou V

Quantification of Neural Ethanol and Acetaldehyde Using Headspace GC-MS.

使用顶空 GC-MS 定量神经乙醇和乙醛。

DOI：
发表时间：
2016-09
期刊：
影响因子：
0
作者：
Heit, Claire;Eriksson, Peter;Thompson, David C;Charkoftaki, Georgia;Fritz, Kristofer S;Vasiliou, Vasilis
通讯作者：
Vasiliou, Vasilis

Glutathione deficiency-elicited reprogramming of hepatic metabolism protects against alcohol-induced steatosis.

谷胱甘肽缺乏引起的肝脏代谢重新编程可以防止酒精引起的脂肪变性。

DOI：
10.1016/j.freeradbiomed.2019.07.025
发表时间：
2019-07-24
期刊：
Free radical biology & medicine
影响因子：
7.4
作者：
Ying Chen;S. Manna;Srujana Golla;K. Krausz;Yan Cai;R. Garcia;T. Chakraborty;Joyeeta Chakraborty;R. Chatterjee;D. Thompson;F. Gonzalez;Vasilis Vasillou
通讯作者：
Vasilis Vasillou

Associations between per- and polyfluoroalkyl substances, liver function, and daily alcohol consumption in a sample of U.S. adults.

美国成年人样本中全氟烷基物质和多氟烷基物质、肝功能和每日饮酒量之间的关联。