Proteomic Investigations of Alcoholic Hepatitis

描述（由申请人提供）：过度饮酒是一个主要的全球公共卫生问题，酒精性肝病（ALD）是美国肝脏相关死亡的主要原因。酒精性肝炎（AH），在一生中的发生率高达20%，是一种 特别是严重的ALD，短期死亡率高。这项工作的重点是应用灵敏的液相色谱-质谱（LC-MS）平台的广泛检测和定量的蛋白质丰度对AH的分子机理研究。在将蛋白质组学技术应用于肝脏相关疾病的研究方面，已经进行了大量的先前工作，但其尚未在临床上应用于肝脏相关疾病的研究。 调查啊。这些技术能够提供关键生物流体、细胞和组织的公正观点，其中对AH的发病机制、疾病进展的分子特征以及重要的是可以帮助确定治疗结果和评估新治疗方案的任何特征的理解有限。我们将应用基于发现和验证的蛋白质组学技术，结合使用血浆、肝组织和分离的循环血细胞的临床试验，对AH进行研究，以确定接受皮质类固醇和抗细胞因子治疗的患者的表达和/或分泌蛋白质的差异集。本研究的目的是确定和验证关键分子标志物和整合途径，以阐明对AH疾病进展机制和潜在治疗效果的理解。相关性，整合和功能映射的蛋白质水平的结果与整个U 01财团进行的补充研究将提供重要的背景下，在系统水平的初步发现和解释。

DESCRIPTION (provided by applicant): Excessive alcohol consumption is a major global public health issue, with alcoholic liver disease (ALD) being a leading cause of liver-related death in the United States. Alcoholic hepatitis (AH), at up to a 20% lifetime occurrence rate, is a particularly serious form of ALD with high short term mortality rates. This work focuses on the application of sensitive liquid chromatography-mass spectrometry (LC-MS) platforms for the broad detection and quantification of protein abundances towards the molecular mechanistic study of AH. Significant previous work has been performed in the application of proteomic technologies towards the study of liver related diseases, but it has not been applied clinically to investigate AH. Such technologies have the ability to provide an unbiased view of key biofluids, cells, and tissues, where there is limited understanding concerning the mechanistic onset of AH, the molecular signatures of disease progression, and importantly any signatures which can help determine treatment outcomes and assess new treatment regiments. We will apply both discovery and verification-based proteomic technologies towards the investigation of AH in conjunction with a clinical trial using blood plasma, liver tissue, and isolated circulating blood cells, to determine the differentiating set of expressed and/or secreted proteins for patients undergoing corticosteroid and anti-cytokine treatment. The goals of this study will be to identify and verify key molecular markers and integrated pathways which would clarify understanding of the mechanism of AH disease progression and potential treatment effects. Correlation, integration, and functional mapping of the protein-level results with complementary studies performed across the U01 consortium will provide important context to initial findings and interpretations at the systems level.