Lipid Aldehyde and Ethanol Induced Liver Damage

酒精性肝病（ALD）是美国发病率和死亡率的重要来源。ALD为 进行性疾病，包括肝脂肪变性、脂肪性肝炎、纤维化和肝硬化。人们普遍 公认的ALD的分子机制是多因素的，包括抗氧化剂受损， 系统和具有改变肝细胞的潜力的反应性氧化剂种类的过度产生 脂质、蛋白质和核酸。氧化剂介导的脂质修饰以及由此产生的修饰 肝细胞稳态的关键蛋白质，是重要的机制事件，有助于 ALD的开始和/或进展。所提出的实验的工作假设是 集中在命题，蛋白质修饰发生的结果，脂质过氧化，蛋白质 糖基化或乙酰化是ALD发病机制中的重要事件。在过去的融资中 在这次优异奖期间，在完善和发展先进技术方面取得了重大进展， 蛋白质组学方法用于分离、鉴定和功能性表征被修饰的蛋白质， 脂质过氧化产物4-羟基壬烯醛（4-HNE）。在发展方面也取得了重大进展 的小鼠和大鼠模型的ALD，以探测肝失调相关的特定成分， 氧化应激此外，使用生物信息学方法来识别代谢组分 开发了受酒精诱导的氧化应激影响的途径和生物系统。这些 我们将在以下三个具体方面采用综合实验方法来检验我们的工作假设 目的：Aiml的实验将继续表征酒精诱导的功能性后果。 使用我们最近的研究， 开发了小鼠模型，其显示从脂肪变性到脂肪性肝炎的可预测进展。研究 目的2将使用我们最近开发的PPARa，GSTA 4 -4双KO鉴定修饰的蛋白质组 小鼠目的3将通过评估ALD中修饰的蛋白质组来探讨自身免疫在ALD进展中的作用。 B6.12957-Rag 1小鼠以及三重KO B6.12957-Rag 1-PPARa-GSTA 4 -4小鼠，以帮助识别 参与免疫反应的机制。总的来说，来自于 这些实验将为减轻ALD的新治疗策略提供新的见解。

Alcoholic liver disease (ALD) is a significant source of morbidity and mortality in the United States. ALD is a progressive disease encompassing hepatic steatosis, steatohepatitis, fibrosis and cirrhosis. It is widely accepted the molecular mechanisms underlying ALD are multifactorial including compromised antioxidant systems and the overproduction of reactive oxidant species having the potential to modify hepatocellular lipids, proteins and nucleic acids. The oxidant-mediated modification of lipids, and the resulting modification of key proteins critical for hepatocellular homeostasis, are important mechanistic events contributing to initiation and/or progression of ALD. The working hypothesis underlying the proposed experiments is focused on the proposition that protein modification occurring as a consequence of lipid peroxidation, protein glycosylation or acetylation are significant events in the pathogenesis of ALD. During the previous funding period of this MERIT AWARD, significant progress was made in refinement and development of state-of-theart proteomic approaches for isolating, identifying and functionally characterizing proteins modified by the lipid peroxidative products 4-hydroxynonenai (4-HNE). Significant progress was also made in development of mouse and rat models of ALD to probe specific components of hepatic dysregulation associated with oxidative stress. In addition, the use of bioinformatic approaches to identify components of metabolic pathways and biologic systems impacted by alcohol-induced oxidative stress were developed. These combined experimental approaches will be used to test our working hypothesis in the following three specific aims: Experiments in Aiml will continue characterization of the functionai consequences of alcohol-induced changes in the hepatic proteome resulting from 4-HNE, glycsoylation or acetylation using our recentiy developed mouse models which displays predictable progression from steatosis to steatohepatitis. Studies in Aim 2 will identify the modified proteomes using our recentiy developed PPARa, GSTA4-4 double KO mice. Aim 3 will explore the role of autoimmunity in progression of ALD by evaluating modified proteomes in B6.12957-Rag1 mice as well as the triple KO B6.12957-Rag1- PPARa-GSTA4-4 mice to aid in identification of mechanisms involved in the immune response. Collectively, the mechanistic information derived from these experiments will provide new insight into novel therapeutic strategies to attenuate ALD.