权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

LncRNA H19 in Cholestatic Liver Diseases

LncRNA H19 在胆汁淤积性肝病中的作用

基本信息

批准号：
10909545
负责人：
PHILLIP B HYLEMON
金额：
$ 62.96万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-25 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10909545
关键词：
Algorithms Animal Model Bile Acids Biliary Bioinformatics Biological Process Ceramides Characteristics Cholestasis Clinical Code Data Diagnostic Disease Epidermal Growth Factor FDA approved Family member Fibrosis Functional disorder Funding Gene Expression Gene Expression Regulation Genes Genetic Transcription Goals H19 gene HMGB1 gene Hepatic Hepatic Stellate Cell High-Throughput RNA Sequencing Human Human Genome Impairment Inflammation Inflammatory Injury Kupffer Cells Ligation Liver Liver Fibrosis Liver diseases MLLT2 gene Macrophage Mediating Metabolism MicroRNAs Molecular Morbidity - disease rate Mus Pathogenicity Pathologic Processes Pathway interactions Patients Pattern Physiological Processes Play Porifera Proliferating Proteins Publishing RNA analysis Reporting Role Sampling Sequence Analysis Serum Severities Sphingolipids Sphingosine Taurocholic Acid Testing Therapeutic Tissues Untranslated RNA Up-Regulation bile duct bile formation cholangiocyte circular RNA clinical application human disease innovation liver inflammation liver injury mammalian genome mortality mouse model new therapeutic target novel diagnostics overexpression primary sclerosing cholangitis promoter receptor senescence single nucleus RNA-sequencing stellate cell transcriptome transcriptome sequencing

项目摘要

Primary sclerosing cholangitis (PSC) is the major cholestatic liver disease with high morbidity and mortality. Inflammation and fibrotic injury of the bile ducts due to impairment of bile formation or flow represent the major characteristics of PSC. The majority of the mammalian genome are non-protein-coding sequences. Less than 2% of the human genome is made up of protein-coding genes. A large fraction of the transcribed mammalian genome is noncoding RNAs (ncRNAs), including long noncoding RNAs (lncRNAs), circular RNA (circRNAs), and microRNA (miRNAs), but only a few of them have been structurally annotated. The biological functions of ncRNAs remain largely unknown. Recent advances in high-throughput RNA sequencing (RNAseq) and circRNA- specific bioinformatics algorithms have identified thousands of circRNAs with tissue-specific expression patterns. However, the relevance and function of circRNAs in disease, especially in liver diseases, remain to be determined. Our previous studies reported that the conjugated primary bile acid (CBA), taurocholic acid (TCA), activated sphingosine-1phosphate receptor 2 (S1PR2) and induced H19 expression in cholangiocytes. TCA- induced upregulation of H19 is a major promoter of cholestatic liver injury by activating inflammatory macrophages and hepatic stellate cells (HSCs). Our new preliminary data using Arraystar circRNAseq identified 33 overlapping circRNAs, which were significantly upregulated in Mdr2-/- mice and downregulated in Mdr2-/-/H19- /- mice. Among them, mmu_circRNA_26644 (circRNA-Edil3), which is encoded by epidermal growth factor-like repeats and discoidin I-like domains 3 (Edil3) gene, is the most significantly downregulated circRNA in Mdr2-/- /H19-/- mice. Sequence analysis suggested that circRNA-Edil3 may serve as a "sponge" for miRNA-215-3p, miRNA-129-5p and miRNA-3075-3p. TargetScan analysis suggested that High Mobility Group Box Protein 1 (HMGB1), AF4/FMR2 Family Member 3 (Aff3) and Edil3 are potential targets of miRNA-215-3p, miRNA-129-5p and miRNA-3075. Based on our published results and exciting new preliminary data, we HYPOTHESIZE that H19-induced upregulation of circRNA-Edil3 plays a critical role in cholestatic liver injury by sequestering miRNAs. Two specific aims are proposed to test our hypothesis. Aim 1. To examine the role of H19-induced circRNA-Edil3 in regulating cholangiocyte proliferation, senescence and hepatic inflammation using cholestatic liver injury mouse models and human PSC patient liver and serum samples. Aim 2: To identify the mechanisms by which H19-induced circRNA-Edil3 promotes cholestatic liver injury. We will use multiple newly-established approaches and animal models to test our hypothesis. Completion of these specific aims should elucidate the potential cellular/molecular mechanisms involved in lncRNA H19-mediated progression of cholestatic liver diseases and identify novel diagnostic and therapeutic targets. Since the effects of cholestasis are profound and widespread, leading to worsening liver diseases and systemic illness, the subject matter of this proposal is timely, important, and has direct clinical application.

原发性硬化性胆管炎（PSC）是主要的胆汁淤积性肝病，发病率和死亡率高。