Genomic and Metabolomic Responses to Alcohol-induced Liver Damage

对酒精性肝损伤的基因组和代谢组反应

• 批准号: 8048395
• 负责人: Albert J Fornace
• 金额: $ 30.22万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-15 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8048395
• 关键词: Abbreviations; Adverse effects; Alcohol consumption; Alcohol dehydrogenase; Alcohol-Induced Disorders; Alcoholic Liver Diseases; Alcoholic liver damage; Alcohols; Animal Model; Biological Markers; Cause of Death; Cirrhosis; Clinical; Collaborations; Coupled; Cytochrome P450; Development; Diet; Discriminant Analysis; Disease; Disease Progression; Early Diagnosis; Employee Strikes; Epigenetic Process; Exhibits; Fatty Liver; Feces; Fibrosis; Gene Expression; Gene Expression Profiling; Genomics; Goals; Hepatic; Hepatocyte; Hepatomegaly; Human; Impairment; Inflammation; Intervention; Knockout Mice; Laboratories; Lead; Life Style; Link; Liquid Chromatography; Liver; Liver diseases; Mass Spectrum Analysis; Metabolic; Methylation; MicroRNAs; Modeling; Monitor; Mus; NADH; National Cancer Institute; Nicotinamide adenine dinucleotide; Nonesterified Fatty Acids; Nuclear Receptors; Obesity; PPAR alpha; Pathogenesis; Pathway interactions; Performance; Peroxisome Proliferator-Activated Receptors; Peroxisome Proliferators; Polymerase Chain Reaction; Post-Translational Protein Processing; Prevention; Principal Component Analysis; Publications; Reactive Oxygen Species; Regulation; Response Elements; Role; Serum; Stress; Structure; System; Therapeutic Intervention; Time; Toxicogenomics; United States; Universities; alcohol response; aldehyde dehydrogenases; attenuation; base; burden of illness; chromatin immunoprecipitation; chronic alcohol ingestion; clinical application; design; disease diagnosis; experience; feeding; human subject; metabolomics; mouse model; oxidation; programs; promoter; toxicant; urinary

DESCRIPTION (provided by applicant): Alcohol consumption contributes to 4% of the global disease burden and in the United States is the third leading lifestyle-related cause of death due in part to complications arising from alcohol-induced liver disease (ALD). In addition to obesity, chronic alcohol consumption leads to excessive hepatic free fatty acid (FFA) levels that inhibit ¿-oxidation pathways and ultimately cause liver disease (steatosis, inflammation, hepatomegaly, fibrosis, and cirrhosis). Interestingly, the adverse effects of alcohol on the liver, in humans and in mouse models, appear to be due, in part, to attenuation of the peroxisome-proliferator activated receptor alpha (PPARa). The alcohol-fed Ppara-null mouse serves as an excellent model for ALD observed in humans and underscores the importance of PPARa in protecting against ALD. Additionally, this mouse model has been cited in over 750 publications supporting its significant utility in understanding the role of PPARa. The mechanism of the influence of PPARa will be determined for potential therapeutic intervention strategies on ALD and for the development of biomarkers for early detection of this disease. To this end, the following specific aims were designed: 1) To correlate alcohol-induced liver damage with gene expression and metabolomic biomarkers identified in alcohol-fed Ppara-null mice for the purpose of developing specific ALD biomarkers.; 2) To identify potential epigenetic and post-transcriptional changes associated with decreased PPARa expression in mouse models following alcohol consumption; and 3) To develop toxicogenomic and toxicometabolomic signatures for types of alcohol-induced injury using primary hepatocyte cultures. These aims seek to understand and integrate the histopathological, genomic, and metabolomic alterations associated with ALD for the purpose of developing early biomarkers associated with ALD pathogenesis. Chronic alcohol consumption can lead to alcohol-induced liver damage (ALD) due to the impairment of ¿-oxidation pathways and subsequent development of fatty liver. A key regulator of ¿-oxidation is the peroxisome-proliferator activated receptor alpha (PPARa). Alcohol-fed mice lacking PPARa develop human-like ALD and in this project will be used to develop biomarkers that are indicative of ALD progression.

描述（由申请人提供）： 饮酒占全球疾病负担的 4%，在美国，饮酒是与生活方式相关的第三大死亡原因，部分原因是酒精性肝病 (ALD) 引起的并发症。除了肥胖之外，长期饮酒还会导致肝脏游离脂肪酸（FFA）水平过高，从而抑制β-氧化途径，最终导致肝脏疾病（脂肪变性、炎症、肝肿大、纤维化和肝硬化）。有趣的是，在人类和小鼠模型中，酒精对肝脏的不利影响似乎部分归因于过氧化物酶体增殖物激活受体α（PPARa）的减弱。酒精喂养的 Ppara-null 小鼠是在人类中观察到的 ALD 的优秀模型，并强调了 PPARa 在预防 ALD 方面的重要性。此外，该小鼠模型已在 750 多篇出版物中被引用，支持其在理解 PPARa 作用方面的重要作用。 PPARα 的影响机制将被确定，以用于 ALD 的潜在治疗干预策略，并开发用于早期检测该疾病的生物标志物。为此，设计了以下具体目标：1）将酒精引起的肝损伤与在酒精喂养的 Ppara-null 小鼠中鉴定的基因表达和代谢组生物标志物关联起来，以开发特定的 ALD 生物标志物。 2) 鉴定与饮酒后小鼠模型中 PPARa 表达降低相关的潜在表观遗传和转录后变化； 3) 利用原代肝细胞培养物开发酒精引起的损伤类型的毒理学和毒代谢特征。这些目标旨在了解和整合与 ALD 相关的组织病理学、基因组和代谢组学改变，以开发与 ALD 发病机制相关的早期生物标志物。长期饮酒会因 β-氧化途径受损而导致酒精性肝损伤 (ALD)，并随后发展为脂肪肝。 β-氧化的关键调节剂是过氧化物酶体增殖物激活受体α (PPARa)。缺乏 PPARa 的酒精喂养小鼠会出现类似人类的 ALD，在该项目中将用于开发指示 ALD 进展的生物标志物。