Developmental pathways, environmental agents, and epigenetics in liver disease

肝病的发育途径、环境因素和表观遗传学

基本信息

批准号：
8688852
负责人：
Chen Liu
金额：
$ 59.13万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-20 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8688852
关键词：
Aberrant DNA Methylation Acetaldehyde Address Aflatoxins Alcohol abuse Alcohol consumption Alcoholic Liver Diseases Alcohols Apoptosis Behavior Bioinformatics Biological Assay Biological Markers Blood Cancer Etiology Cell Culture System Cell Cycle Cessation of life ChIP-on-chip Chronic Cirrhosis Clinical Complex Country Coupled Coupling CpG Islands Custom DNA Methylation DNA biosynthesis Data Defect Development Developmental Gene Developmental Process Diagnosis Diagnostic Diet Disease Disease Progression Environment Epigenetic Process Ethanol Etiology Event Gene Expression Profile Gene Silencing Genes Genetic Genetic Transcription Genome Stability Growth HCV Liver Disease Hepatitis B Hepatitis C Hepatitis C virus Hepatocyte Histone Code Histones Homeobox Genes Human In Vitro Incidence Infection Infectious Agent Inflammation Knowledge Lead Lesion Linear Regressions Link Liver Liver Cirrhosis Liver diseases Malignant Neoplasms Mediating Methylation Modeling Molecular Natural History Ontology Pathogenesis Pathway interactions Patients Pattern Play Polycomb Predisposing Factor Premalignant Primary carcinoma of the liver cells Prognostic Marker Quality of life Recovery Recreational Drugs Regulation Regulator Genes Resected Resources Risk Role Sampling Small Interfering RNA System Techniques Testing Time Tissue Banking Tissue Banks Tissues United States Virus alcohol effect alcohol exposure base cell growth cell motility chronic liver disease design environmental agent epigenome genome-wide hepatocellular carcinoma cell line histone modification improved liver injury neoplastic cell novel outcome forecast promoter recreational drug abuse tissue culture tool tumor

项目摘要

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is the 5th most common cancer worldwide, causing an estimated 600,000 deaths/yr. Alcohol abuse and hepatitis C virus (HCV) infection cause inflammation and chronic liver diseases, including cirrhosis, and synergistically increase risk for HCC. Cirrhosis is a well-defined precancerous lesion, yet its molecular underpinnings at the level of the epigenome have not been examined. Alcohol consumption is rising in many countries and results in ~1.8 million deaths/yr. Approximately 170 million people worldwide are infected with HCV, 4 million in the United States, making it the most common blood-borne disease in the U.S. The etiologic agents responsible for the majority of HCCs (>85%) are perhaps better understood than for any other cancer, and all are due to environmental agents or human behaviors (e.g. alcohol, HCV), yet there is much that we do not understand about how these agents exert their carcinogenic effects over >30 years with significant clinical variability. There is no definitive evidence for alcohol or HCV directly mediating genetic damage. There is mounting evidence, however, for early and progressive epigenetic changes during liver disease and for a role of diet and inflammation in disrupting the epigenome. Based on studies from our group and others, genes regulating development appear to be one of the preferential targets of epigenetic defects in cancers, including HCC. A comprehensive analysis of the epigenetic regulation of developmental pathways has never been performed in normal or diseased liver, limiting our knowledge of the full extent and timing of epigenetic changes in the etiology of human liver disease and how these changes may be used as prognostic markers to improve treatment. We hypothesize that epigenetic changes in developmental pathways caused by chronic alcohol exposure and/or HCV infection play a key role in the pathogenesis of liver disease, HCV-induced cellular damage, and HCC development. We propose four aims to address this hypothesis. In aim 1 we will epigenetically profile human liver tissues from patients with cirrhosis or HCC caused by alcohol and/or HCV by coupling a large liver tissue bank with a custom tiling array focused on developmental regulatory genes. In aim 2 we will epigenetically profile untreated and alcohol treated/HCV infected primary hepatocytes using a cell culture system. In aim 3 we will confirm our array data with sensitive and quantitative assays and examine the mechanisms by which ethanol/HCV modulate epigenetic control of model developmental genes and how aberrant expression of developmental genes regulates cell growth. Finally, in aim 4 we will examine how epigenetic marks/expression of developmental genes relates to clinical and pathological changes during liver disease progression. Results from these studies are expected to greatly enhance our understanding of the epigenetic etiology of HCC, provide new targets for therapy and diagnosis/prognosis, and yield novel information on how a ubiquitous recreational drug and a widespread infectious agent impact the epigenome.

描述（由申请人提供）：肝细胞癌 (HCC) 是全球第五大常见癌症，估计每年导致 600,000 人死亡。酗酒和丙型肝炎病毒 (HCV) 感染会导致炎症和慢性肝病，包括肝硬化，并协同增加患 HCC 的风险。肝硬化是一种明确的癌前病变，但其表观基因组水平的分子基础尚未得到检验。许多国家的酒精消费量正在上升，每年导致约 180 万人死亡。全球大约有 1.7 亿人感染 HCV，其中美国有 400 万人感染 HCV，使其成为美国最常见的血源性疾病。对导致大多数 HCC (>85%) 的病因可能比任何其他疾病都更了解。其他癌症，所有这些都是由环境因素或人类行为（例如酒精、丙型肝炎病毒）引起的，但我们对这些因素如何在超过 30 年的时间里发挥其致癌作用以及显着的临床变异性还有很多不了解的地方。没有明确的证据表明酒精或丙型肝炎病毒直接介导遗传损伤。然而，越来越多的证据表明，肝病期间存在早期和进行性的表观遗传变化，以及饮食和炎症在破坏表观基因组方面的作用。根据我们小组和其他人的研究，调节发育的基因似乎是癌症（包括肝癌）表观遗传缺陷的优先目标之一。从未在正常或患病肝脏中对发育途径的表观遗传调控进行全面分析，这限制了我们对人类肝脏疾病病因学表观遗传变化的全面程度和时间以及如何将这些变化用作预后标志物的了解。改善治疗。我们假设，慢性酒精暴露和/或 HCV 感染引起的发育途径的表观遗传变化在肝病、HCV 诱导的细胞损伤和 HCC 发展的发病机制中发挥着关键作用。我们提出四个目标来解决这一假设。在目标 1 中，我们将通过将大型肝脏组织库与专注于发育调节基因的定制平铺阵列相结合，对来自酒精和/或 HCV 引起的肝硬化或 HCC 患者的人类肝脏组织进行表观遗传学分析。在目标 2 中，我们将使用细胞培养系统对未经处理和酒精处理/HCV 感染的原代肝细胞进行表观遗传学分析。在目标 3 中，我们将通过敏感和定量测定来确认我们的阵列数据，并检查乙醇/HCV 调节模型发育基因的表观遗传控制的机制以及发育基因的异常表达如何调节细胞生长。最后，在目标 4 中，我们将研究发育基因的表观遗传标记/表达与肝病进展过程中的临床和病理变化之间的关系。这些研究的结果预计将大大增强我们对 HCC 表观遗传学病因学的理解，为治疗和诊断/预后提供新的靶标，并提供关于普遍存在的娱乐性药物和广泛的传染原如何影响表观基因组的新信息。