Novel prognostic microRNA biomarkers for primary sclerosing cholangitis

描述（由申请人提供）：原发性硬化性胆管炎（PSC）是一种病因不明的进行性慢性胆汁淤积性肝病。PSC以胆管炎症和破坏为特征，常发展为晚期活体疾病，如肝硬化、肝癌和肝功能衰竭。由于没有有效的治疗选择，肝移植目前被认为是PSC的唯一治疗选择，PSC患者的5年生存率为86%。然而，由于psc相关的肝胆恶性肿瘤的高风险，肝移植的最佳时机难以确定。PSC的进展通常通过内窥镜逆行胰胆管造影（ERCP）和肝活检来监测；侵入性手术会增加严重并发症的风险。因此，一种监测PSC进展的非侵入性工具仍然是一个未满足的医疗需求。MicroRNAs （miRNAs）是一种小的非编码rna，通过与信使rna (mRNA) 3'非翻译区部分互补的靶序列配对，促进mRNA降解和/或阻断翻译，从而负向调节基因表达。最近的研究表明，在包括HCC、HBV和肝硬化在内的多种肝脏疾病和病理患者中，许多循环血清miRNA水平升高。因此，血清miRNAs是几种肝脏疾病的新型诊断和预后生物标志物。虽然PSC的血清miRNA生物标志物尚未开发用于临床应用，但我们的初步概念验证研究确定了血清miRNA特征亚群，这些亚群在PSC进展和相关并发症中具有独特的表达模式。在这里，我们建议在一个更大的独立PSC队列中验证这些初步结果，并使用尖端的下一代RNA-seq技术确认血清miRNA特征与肝脏中miRNA和靶基因表达的关系。我们将在一项适当的研究中确认从病变肝脏释放的血清PSC miRNA生物标志物的敏感性和特异性，以预测晚期PSC。这些建议的研究是可行的，代表了开发用于PSC诊断和预后临床应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确定PSC进展和PSC相关肝胆恶性肿瘤发展的新机制。

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.