Transcriptomics of Liver in Alcoholic Hepatitis

描述(申请人提供)：本部分建议的实验旨在确定酒精性肝炎肝脏的转录组的特征，并确定作为疾病严重程度、治疗反应和预后标志的表达基因和转录本。完整的转录本将使用RNA-seq技术进行测量。两个假设是拟议实验的基础。酒精性肝炎患者肝脏转录本具有可测量的定量表达特征，区别于酒精性肝硬变患者和正常肝组织的转录本。酒精性肝炎患者的临床特征、治疗反应和预后可归因于其肝组织转录本的变化。此外，表达标记将与生物相关的蛋白质组标记相关联。我们将测量30例酒精性肝炎患者的肝组织样本，其中30例酒精性肝炎患者的Lille评分为0.45，30例酒精性肝炎患者的Lille评分为0.45，30例酒精性肝硬变患者和30例匹配的正常样本的转录本，以确定酒精性肝炎的特异性转录图谱。在这项工作的同时，我们将测量参加临床试验的150名酒精性肝炎患者的肝组织转录本，并确定与治疗相关的临床结果和预后的基因和转录表达标记物。这项工作将产生一系列转录本、基因、功能突变、通路和基因-蛋白质网络，这些转录本、基因、功能突变和基因-蛋白质网络是酒精性肝炎的特征，也是酒精性肝炎患者临床结果和预后的标志。虽然这个项目在很大程度上是不可知的和基于发现的，但它是一个重要的转化性研究，高度补充了财团中的其他U01项目。我们将在酒精性肝炎肝脏转录组中鉴定酒精性肝炎的基因和转录表达标志物，并鉴定治疗反应和预后的标志物。

DESCRIPTION (provided by applicant): The experiments proposed in this component are designed to characterize the transcriptome of the alcoholic hepatitis liver and identify expressed genes and transcripts that are markers of disease severity, response to treatment and prognosis. Full transcriptomes will be measured using RNA-seq technology. Two hypotheses are the basis of the proposed experiments. The transcriptomes of livers from alcoholic hepatitis patients have measureable quantitative expression characteristics that distinguish them from the liver transcriptomes of alcoholic cirrhosis patients and healthy liver tissue. The clinical features, treatment response and prognosis of alcoholic hepatitis patients can be attributed to variation in the transcriptomes of their liver tissue. Furthermore, the expression markers will be correlated with biologically related proteomic markers. We will measure the transcriptomes of liver tissue samples taken from 30 alcoholic hepatitis patients with Lille scores < 0.45, 30 alcoholic hepatitis patients with Lille scores e 0.45, 30 alcoholic cirrhosis patients, and 30 matched normal samples to identify an alcoholic hepatitis-specific transcription profile. In parallel with this work, we will measure the transcriptomes of liver tissue sampled from 150 alcoholic hepatitis patients at enrollment in a clinical trial and identify gene and transcript expression markers of treatment-related clinical outcomes and prognosis. This work will generate sets of transcripts, genes, functional mutations, pathways, and gene-protein networks that are characteristic of alcoholic hepatitis and markers for the clinical outcomes and prognosis of alcoholic hepatitis patients. Although this project is largely agnostic and discovery-based it i important translational research that highly complements the other U01 projects in the consortium. We will identify gene and transcript expression markers of the alcoholic hepatitis liver and identify markers of treatment response and prognosis in the alcoholic hepatitis liver transcriptome.