LncRNA H19 in Cholestatic Liver Diseases

LncRNA H19 在胆汁淤积性肝病中的作用

• 批准号: 9750721
• 负责人: PHILLIP B HYLEMON
• 金额: $ 53.65万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-25 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750721
• 关键词: Apical; Bile Acids; Bile Duct Epithelium; Biliary; Biological Process; Carbon Tetrachloride; Carcinoma; Cell Proliferation Regulation; Characteristics; Cholestasis; Chronic; Code; Data; Disease; Ductal Epithelial Cell; Epithelial; Exons; Fibrosis; Functional disorder; Gene Expression; Genes; Genetic Transcription; Goals; Growth; H19 gene; Hepatic; Hepatobiliary; Hepatocyte; Homeostasis; Human; Inflammation; Injury; Knock-out; Life Cycle Stages; Ligation; Link; Liver; Liver diseases; Maintenance; Mediating; Messenger RNA; Metastatic Neoplasm to the Liver; Minority; Multi-Drug Resistance; Mus; Output; Pathogenesis; Patients; Physiological; Play; Primary biliary cirrhosis; Proteins; RNA Splicing; Regulation; Regulator Genes; Reporting; Role; Sodium; Sphingosine-1-Phosphate Receptor; Structure; Taurine Cholate; Taurocholate Sodium; Testing; Tissues; Translations; Untranslated RNA; Up-Regulation; base; bile acid transporter; bile duct; cell type; cholangiocyte; cholestatic injury; cholestatic liver disease; chromatin modification; differential expression; effective therapy; human disease; imprint; knock-down; liver development; liver injury; mammalian genome; mouse model; novel; novel strategies; novel therapeutics; polypeptide; prevent; primary sclerosing cholangitis

Cholangiopathies, such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), are characterized by damage and dysfunction of bile duct epithelial cells (cholangiocytes). Recently, long noncoding RNAs (lncRNAs) have been identified as a novel class of master regulators of gene expression and are linked to many fundamental biological processes and various human diseases including various liver diseases. However, little is known regarding the role of lncRNAs in the regulation of cholangiocyte function and pathogenesis of hepatobiliary diseases. The overall goal of the current application is to identify the roles and mechanisms of lncRNAs in biliary dysfunction under cholestatic conditions and to create a fundamental base for developing novel therapeutic strategies for cholangiopathies. The expression of lncRNAs is tissue-, cell type- and differentiation stage-specific. LncRNA H19 is the first identified imprinted lncRNA and is highly conserved across lineages. It has been reported that H19 is the most strongly differentially expressed lncRNA during liver development and has been linked to hepatic metastases from a range of human carcinomas and cholestatic liver injury. However, the regulatory role of H19 in cholangiocyte pathophysiology remains unknown and is the focus of the current application. Our most recent studies discovered that H19 is highly expressed in cholangiocytes, but not in hepatocytes under physiological conditions and hepatic H19 expression levels are correlated with upregulation of S1PR2 and cholestatic liver injury in the multi-drug resistance 2 knockout (Mdr2-/-) mouse, a well- established mouse model of PSC and PSC patient liver. Our preliminary data further showed that 1) BDL significantly up-regulated H19 and down-regulated the apical sodium bile acid transporter (ASBT) and sodium/taurocholate co-transporting polypeptide (NTCP); 2) BDL-induced cholestatic liver injury was markedly reduced in H19ΔExon1/+ mouse; 3) Knocking down H19 not only significantly reduced taurocholate (TCA)- induced expression of fibrotic genes and S1PR2 in cholangiocytes, but also markedly upregulated hepatic small heterodimer partner (SHP) expression and reduced cholestatic injury in Mdr2-/- mice; 4) Hepatic H19 level was also significant upregulated in the carbon tetrachloride (CCl4)-induced cholestatic liver injury mouse model. Based on these observations, we HYPOTHESIZE that lncRNA H19 plays an important role in the regulation of hepatobiliary epithelial function by disruption of hepatic bile acid homeostasis. Two specific aims are proposed to test this hypothesis. 1) To define the role of lncRNA H19 in the regulation of bile acid-mediated cholangiocyte growth and remodeling during cholestatic liver injury; 2) To identify the mechanisms by which bile acids upregulate lncRNA H19 in cholestatic conditions. Completion of the proposed studies will make a significant conceptual advance by linking the lncRNA H19-mediated regulation of biliary epithelial function with cholestatic biliary injury in patients with cholangiopathies and will provide a translational mechanism for how bile acids and lncRNA H19 mediate hepatobiliary fibrosis.

胆管病，如原发性胆汁性肝硬化（PBC）和原发性硬化性胆管炎（PSC），是 其特征在于胆管上皮细胞（胆管细胞）的损伤和功能障碍。最近，长非编码 RNA（lncRNA）已被鉴定为一类新的基因表达的主调节因子，并且与 许多基本的生物过程和各种人类疾病，包括各种肝脏疾病。 然而，关于lncRNA在胆管细胞功能调节中的作用知之甚少， 肝胆疾病的发病机制。当前应用程序的总体目标是确定角色， lncRNA在胆汁淤积条件下的胆道功能障碍中的作用机制，并为 开发新的胆管病治疗策略。lncRNA的表达是组织，细胞类型， 和分化阶段特异性。lncRNA H19是第一个被发现的印迹lncRNA，高度保守 跨越血统据报道，H19是肝脏中差异表达最强的lncRNA， 并与一系列人类癌和胆汁淤积性肝的肝转移有关 损伤然而，H19在胆管细胞病理生理学中的调节作用仍然是未知的，并且是焦点。 当前的应用程序。我们最近的研究发现H19在胆管细胞中高度表达， 但在生理条件下在肝细胞中不存在，并且肝H19表达水平与 在多药耐药2基因敲除（Mdr 2-/-）小鼠中S1 PR 2的上调和胆汁淤积性肝损伤， 建立PSC小鼠模型和PSC患者肝脏。我们的初步数据进一步表明：1）BDL 显著上调H19，下调顶端胆汁酸钠转运蛋白（ASBT）， BDL诱导的胆汁淤积性肝损伤明显减轻， 在H19Δ外显子1/+小鼠中减少; 3）敲除H19不仅显著减少牛磺胆酸盐（TCA）- 诱导胆管细胞中纤维化基因和S1 PR 2的表达，但也显著上调肝小 异源二聚体伴侣（SHP）表达和减少Mdr 2-/-小鼠胆汁淤积性损伤; 4）肝脏H19水平 在四氯化碳（CCl 4）诱导的胆汁淤积性肝损伤小鼠模型中也显著上调。 基于这些观察结果，我们假设lncRNA H19在调节细胞凋亡中起重要作用。 通过破坏肝胆汁酸稳态来影响肝胆上皮功能。两个具体目标是 来检验这个假设。1)为了明确lncRNA H19在胆汁酸介导的细胞凋亡调控中的作用， 胆汁淤积性肝损伤时胆管细胞的生长和重塑; 2）通过 胆汁酸在胆汁淤积状态下上调lncRNA H19。完成拟议的研究将 通过将lncRNA H19介导的胆管上皮细胞调节与 功能与胆汁淤积性胆道损伤的患者，胆管疾病，并将提供一个翻译机制 胆汁酸和lncRNA H19如何介导肝胆纤维化。