Novel prognostic microRNA biomarkers for primary sclerosing cholangitis

原发性硬化性胆管炎的新型预后 microRNA 生物标志物

• 批准号: 8572103
• 负责人: KRIS KOWDLEY
• 金额: $ 27.51万
• 依托单位: BENAROYA RESEARCH INST AT VIRGINIA MASON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8572103
• 关键词: 3' Untranslated Regions; Accounting; Ancillary Study; Bile duct carcinoma; Binding; Biological Markers; Blood Circulation; Cells; Chronic; Cirrhosis; Clinic; Clinical; Clinical Management; Cytolysis; DNA; Data; Data Analyses; Development; Diagnosis; Diagnostic; Disease; Disease Management; Disease Progression; Dose; Double-Blind Method; Endoscopic Retrograde Cholangiopancreatography; Enrollment; Enzyme Tests; Etiology; Functional RNA; Funding; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Goals; HBV Cirrhosis; Hepatic; Hepatobiliary; Inflammation; Knowledge; Laboratories; Lead; Life; Liver; Liver Cirrhosis; Liver Failure; Liver diseases; Malignant Neoplasms; Medical; Medical center; Membrane; Messenger RNA; MicroRNAs; Molecular; Molecular Profiling; Monitor; National Institute of Diabetes and Digestive and Kidney Diseases; Nucleic Acids; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Placebo Control; Procedures; Prognostic Marker; RNA Degradation; Randomized; Relative (related person); Risk; Role; Sensitivity and Specificity; Serum; Source; Staging; Survival Rate; Technology; Therapeutic; Time; Tissue Sample; Tissues; Translations; Ursodeoxycholic Acid; Virginia; base; bile duct; cohort; effective therapy; gene repression; hepatobiliary cancer; high risk; liver biopsy; liver transplantation; next generation; novel; outcome forecast; particle; primary sclerosing cholangitis; prognostic; public health relevance; repository; tool; transcriptome sequencing; treatment strategy

DESCRIPTION (provided by applicant): Primary sclerosing cholangitis (PSC) is a progressive chronic cholestatic liver disease of unknown etiology. Characterized by inflammation and destruction of bile ducts, PSC often progresses to advanced live disease such as cirrhosis, hepatobiliary cancer and liver failure. Without an effective therapeutic option, liver transplantation is currently considered the only curative option for PSC and results an excellent 5 year survival rate of 86% in PSC patients. However, the optimal timing for liver transplantation is difficult to determine due to high risk of PSC-associated hepatobiliary malignancies. The progression of PSC is commonly monitored by Endoscopic Retrograde Cholangiopancreatography (ERCP) and liver biopsy; invasive procedures associated with increased risk of serious complications. Thus, a non-invasive tool to monitor the progression of PSC remains an unmet medical need. MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression by pairing with partially complementary target sequences in the 3' untranslated regions of messenger RNAs (mRNAs) to promote mRNA degradation and/or block translation. Recent studies have shown that levels of many circulating serum miRNA are elevated in patients with a variety of liver diseases and pathologies including HCC, HBV and liver cirrhosis. Therefore serum miRNAs represent a new type of diagnostic and prognostic biomarker for several liver diseases. Although serum miRNA biomarkers for PSC have not been developed for clinical use, our preliminary proof-of-concept study identified subsets of serum miRNA signatures that have unique expression patterns in PSC progression and associated complications. Here, we propose to validate these initial results in a larger independent PSC cohort and confirm the relationship of the serum miRNA signatures to miRNA and target gene expression in the liver using cutting-edge next-generation RNA-seq technologies. We will confirm the sensitivity and specificity of serum PSC miRNA biomarkers released from diseased liver to predict advanced PSC in an appropriately powered study. The proposed studies are feasible, represent two critical steps in developing novel biomarkers for clinical use for PSC diagnosis and prognosis, and provide a unique opportunity to identify new mechanisms involved in PSC-progression and the development of PSC associated hepatobiliary malignancies.

描述（由申请人提供）：原发性硬化性胆管炎（PSC）是一种进行性慢性胆汁淤积性肝病的疾病。 PSC以炎症和胆管破坏为特征，通常会发展为晚期的活疾病，例如肝硬化，肝胆癌和肝衰竭。如果没有有效的治疗选择，目前肝移植被认为是PSC的唯一治愈方法，在PSC患者中，肝移植的5年生存率为86％。然而，由于PSC相关的肝胆管恶性肿瘤的高风险，很难确定肝移植的最佳时机。 PSC的进展通常通过内窥镜逆行胆管造影（ERCP）和肝活检来监测；与严重并发症风险增加有关的侵入性程序。因此，监测PSC进展的非侵入性工具仍然是未满足的医疗需求。 microRNA（miRNA）是小型非编码RNA，通过与3'未翻译的Messenger RNA（mRNA）中的部分互补的靶序列配对，从而对基因表达进行负调节，从而促进mRNA降解和/或阻滞转换。最近的研究表明，许多肝病，HBV和肝肝硬化等多种肝病和病理的患者中，许多循环血清miRNA的水平升高。因此，血清miRNA代表了几种肝病的一种新型诊断和预后生物标志物。尽管尚未开发用于临床使用的PSC的血清miRNA生物标志物，但我们的初步概念验证研究确定了血清miRNA特征的子集，它们在PSC进展和相关并发症中具有独特的表达模式。在这里，我们建议在更大的独立PSC队列中验证这些初始结果，并使用尖端的下一代RNA-SEQ技术确认血清miRNA特征与miRNA与miRNA和靶基因表达的关系。我们将确认从患病的肝脏中释放出的血清PSC miRNA生物标志物的敏感性和特异性，以预测一项适当动力的研究。拟议的研究是可行的，是开发用于PSC诊断和预后临床使用的新型生物标志物的两个关键步骤，并提供了一个独特的机会来识别参与PSC促进的新机制，并开发了PSC相关的肝脏肝脏恶性肿瘤。