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

• 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
• 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

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）是全球第五大癌症，估计造成600,000例死亡/年。酒精滥用和丙型肝炎病毒（HCV）感染会引起炎症和慢性肝病，包括肝硬化，并协同增加HCC的风险。肝硬化是一种定义明确的癌性病变，但尚未检查其在表观依添水平的分子基础。许多国家/地区的饮酒量正在增加，约180万人死亡/年。 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超过30年的临床可变性超过30年。没有明确的证据表明酒精或HCV直接介导遗传损害。然而，对于肝病期间的早期和进行性表观遗传变化以及饮食和炎症在破坏表观遗传组中的作用，有越来越多的证据。根据我们小组和其他人的研究，调节发育的基因似乎是包括HCC在内的癌症中表观遗传缺陷的优先​​靶标之一。对发育途径的表观遗传调节的全面分析从未在正常或患病的肝脏中进行，从而限制了我们对人肝病病因的全面范围和表观遗传变化的了解，以及如何将这些变化用作预后标记以改善治疗。我们假设由慢性酒精暴露和/或HCV感染引起的发育途径的表观遗传变化在肝病的发病机理，HCV诱导的细胞损伤和HCC发育中起关键作用。我们提出了四个目标，以解决这一假设。在AIM 1中，我们将表观遗传介绍来自肝硬化或HCC患者的人肝组织，通过将大型肝组织库与侧重于发育调节基因的定制瓷砖阵列偶联，通过酒精和/或HCV引起的HCC。在AIM 2中，我们将使用细胞培养系统进行表观遗传介绍未经处理和酒精处理/HCV感染的原发性肝细胞的。在AIM 3中，我们将使用敏感和定量测定确认阵列数据，并检查乙醇/HCV调节模型发育基因的表观遗传控制以及发育基因异常表达如何调节细胞生长的机制。最后，在目标4中，我们将研究发育基因的表观遗传标记/表达如何与肝病进展过程中的临床和病理变化有关。这些研究的结果有望极大地增强我们对HCC表观遗传学学的理解，为治疗和诊断/预后提供了新的靶标，并产生有关无处不在的休闲药物和广泛传染剂如何影响表观遗传组的新信息。