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Epigenetic regulation in liver fibrosis

肝纤维化的表观遗传调控

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要在美国，大约30%的成年人患有非酒精性脂肪性肝病(NAFLD)。NAFLD最初表现为肝脏脂肪变性，进展为非酒精性脂肪性肝炎(NASH)、纤维化，甚至肝硬变或者肝细胞癌。肝纤维化，一种细胞外基质积聚增加的情况肝脏是NASH严重程度的有力指标。在大多数NASH患者中，高卡路里等环境因素饮食和久坐不动的生活方式是疾病发展的主要因素。那些环境线索经常调节表观遗传和转录因子以获得长期效果。在我们的初步研究中，我们已经确定Sirtuin 6(SIRT6)是肝纤维化的关键抑制因子。为了进一步研究SIRT6在人类免疫缺陷中的作用肝纤维化的发病机制，我们计划利用细胞和动物进行体外和体内实验模特们。肝星状细胞通常被认为是细胞外产物的主要贡献者。慢性肝损伤后肝脏中的基质。因此，我们将重点放在肝星状细胞的调节上。分子、细胞和组织水平的SIRT6。预计拟议的病理生理和在这一应用中对肝纤维化的机制研究将揭示关键的途径或网络由SIRT6控制。此外，从这个项目中获得的知识可以帮助开发治疗对肝纤维化的干预。