Epigenetic regulation in liver fibrosis

肝纤维化的表观遗传调控

• 批准号: 10428589
• 负责人: X Charlie Dong
• 金额: $ 45.71万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10428589
• 关键词: Address; Adult; Affect; Alcohols; Animal Model; CCAAT-Enhancer-Binding Proteins; Calories; Cell Death; Cell Line; Cell model; Chromatin; Cirrhosis; Complex; Cues; Data; Deacetylase; Development; Diet; Disease; Disease Progression; Drug toxicity; Environmental Risk Factor; Epigenetic Process; Extracellular Matrix; Family member; Fatty Liver; Fibrosis; Foundations; Functional disorder; Future; General Population; Genes; Genetic; Hepatic; Hepatic Fibrogenesis; Hepatic Stellate Cell; Hepatocyte; Histone Deacetylase; Homologous Protein; Human; In Vitro; Inflammation; Investigation; Knockout Mice; Knowledge; Life; Link; Liver; Liver Fibrosis; Liver diseases; Long-Term Effects; Mission; Molecular; Molecular Profiling; Mus; Obesity; Pathogenesis; Pathway interactions; Patients; Physiological; Play; Prevalence; Prevention; Primary carcinoma of the liver cells; Process; Production; Proteins; Public Health; Regulation; Research; Role; Severities; Signal Transduction; Sirtuins; Testing; Therapeutic Intervention; Tissues; Transgenic Mice; United States National Institutes of Health; Virulence Factors; Virus Diseases; burden of illness; cell type; chronic liver disease; chronic liver injury; common treatment; effective therapy; endoplasmic reticulum stress; epigenetic regulation; epigenomics; experimental study; genetic makeup; glucose metabolism; in vivo; lipid metabolism; liver development; liver injury; migration; mouse model; new therapeutic target; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; sedentary lifestyle; therapeutic development; therapeutically effective; transcription factor; transcriptomics

Project Summary Nonalcoholic fatty liver disease (NAFLD) affects approximately 30% adults in the US. NAFLD initially manifests hepatic steatosis and progresses to nonalcoholic steatohepatitis (NASH), fibrosis, and even cirrhosis or hepatocellular carcinoma. Liver fibrosis, a condition of elevated accumulation of extracellular matrix in the liver, is a strong indicator of NASH severity. In most NASH patients, environmental factors such as high-calorie diets and sedentary lifestyle are primary contributors to the disease development. Those environmental cues often modulate epigenetic and transcription factors to acquire long-term effects. In our preliminary study, we have identified Sirtuin 6 (Sirt6) as a key suppressor of liver fibrosis. To further investigate the role of Sirt6 in the pathogenesis of liver fibrosis, we plan to carry out both in vitro and in vivo experiments using cell and animal models. Hepatic stellate cells are generally considered as a major contributor to the production of extracellular matrix in the liver after chronic liver injury. Therefore, we will focus on the regulation of hepatic stellate cells by Sirt6 at molecular, cellular, and tissue levels. It is expected that the proposed pathophysiological and mechanistic investigation of liver fibrosis in this application will uncover key pathways or network that is controlled by Sirt6. Moreover, the knowledge gained from this project can help develop therapeutic interventions for hepatic fibrosis.

项目摘要 非酒精性脂肪肝（NAFLD）影响美国约30%的成年人。NAFLD最初 表现出肝脂肪变性并进展为非酒精性脂肪性肝炎（NASH）、纤维化甚至肝硬化 或肝细胞癌。肝纤维化是指肝细胞外基质在肝组织中积聚增加的一种情况。 肝脏是NASH严重程度的强指标。在大多数NASH患者中，环境因素如高热量 饮食和久坐不动的生活方式是导致疾病发展的主要因素。那些环境线索 通常调节表观遗传和转录因子以获得长期效应。在初步研究中，我们 已经鉴定Sirtuin 6（Sirt6）为肝纤维化的关键抑制因子。为了进一步研究Sirt6在 肝纤维化的发病机制，我们计划使用细胞和动物进行体外和体内实验， 模型肝星状细胞通常被认为是产生细胞外基质的主要贡献者。 慢性肝损伤后肝内基质的变化。因此，我们将重点关注肝星状细胞的调节， Sirt6在分子、细胞和组织水平上的表达。预期所提出的病理生理学和 在该应用中，肝纤维化的机制研究将揭示肝纤维化的关键途径或网络， 由Sirt6控制此外，从这个项目中获得的知识可以帮助开发治疗 肝纤维化的治疗