Quantitative Proteomic Analysis of Alcoholic Fatty Liver Biogenesis

描述(申请人提供)：在西方世界，长期大量饮酒是导致肝脏疾病和死亡的主要原因。酒精性肝病(ALD)具有较好的临床和形态学特征，可分为三个主要阶段：1)脂肪肝，通常在戒酒后可逆转；2)酒精性肝炎或肝脏炎症；3)肝硬变或肝脏瘢痕形成。ALD的治疗需要新的治疗工具。然而，为了开发这样的治疗方法，需要彻底了解导致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品的全球图谱成为现实。我们建议开发一种定量蛋白质组学策略来确定ALD发生的分子机制。由于疾病发展的三个临床阶段背后的分子机制仍然知之甚少，我们将重点放在疾病的生物发生上：1)确定导致酒精性脂肪性肝病(AFLD)第一阶段ALD的分子机制，2)剖析具体归因于使用 通过与非酒精性脂肪性肝病(NAFLD)的比较分析，以及3)随后选择/表征可区分酒精性和非酒精性脂肪肝的候选蛋白质生物标志物，从而建立早期疾病进展的标志性诊断小组。

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.