Quantitative Proteomic Analysis of Alcoholic Fatty Liver Biogenesis

描述（由申请人提供）：长期大量饮酒是西方世界肝病疾病和死亡的主要原因。酒精性肝病（ALD）在临床和形态学上有很好的特征，并被描述为疾病进展的三个主要阶段：1）脂肪肝，其通常在戒酒后可逆，2）酒精性肝炎或肝脏炎症，以及3）肝硬化或肝脏瘢痕形成。需要新的治疗工具来治疗ALD。然而，为了开发这种疗法，需要彻底了解酒精诱导的肝损伤每个阶段的分子机制。高通量技术的最新发展使差异表达基因产物的全球概况成为现实。我们建议开发一种定量蛋白质组学策略，以确定有助于ALD发展的分子机制。由于疾病进展的三个临床阶段中的每一个的分子机制仍然知之甚少，我们将关注疾病的生物发生：1）确定有助于ALD第1阶段，酒精性脂肪肝（AFLD）的分子机制，2）解剖特别归因于使用药物的机制。 通过与非酒精性脂肪肝疾病（NAFLD）的比较分析来确定酒精，和3）随后选择/表征蛋白质生物标志物候选物，其可以区分酒精性和非酒精性脂肪肝，并导致建立用于早期疾病进展的特征诊断组。

DESCRIPTION (provided by applicant): Long-term heavy alcohol consumption is the leading cause of illness and death from liver disease in the Western world. Alcoholic liver disease (ALD) is well characterized clinically and morphologically and is described in three major stages of disease progression: 1) fatty liver, which is usually reversible with abstinence, 2) alcoholic hepatitis or liver inflammation, and 3) cirrhosis, or scarring of the liver. Novel therapeutic tools are needed for the treatment of ALD. However, to develop such therapies, a thorough understanding of the molecular mechanisms contributing to each stage of alcohol-induced liver injury is required. Recent developments in high-throughput technologies make the global profiling of differentially expressed gene products a reality. We propose to develop a quantitative proteomic strategy to identify the molecular mechanisms contributing to the development of ALD. Because the molecular mechanisms underlying each of the three clinical stages of disease progression are still poorly understood, we will focus on disease biogenesis: 1) the determination of the molecular mechanisms contributing to ALD Stage 1, alcoholic fatty liver disease (AFLD), 2) the dissection of the mechanisms specifically attributed to the use of alcohol by a comparative analysis with nonalcoholic fatty liver disease (NAFLD), and 3) the subsequent selection/characterization of protein biomarker candidates which can distinguish between alcoholic and nonalcoholic fatty liver and lead to the establishment of signature diagnostic panels for early disease progression.