Novel prognostic microRNA biomarkers for primary sclerosing cholangitis

描述（由申请方提供）：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。以胆管炎症和破坏为特征，PSC通常进展为晚期肝病，如肝硬化、肝胆癌和肝功能衰竭。在没有有效治疗选择的情况下，肝移植目前被认为是PSC的唯一治愈选择，并且在PSC患者中获得了86%的极好的5年生存率。然而，由于PSC相关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术（ERCP）和肝活检进行监测;侵入性操作与严重并发症的风险增加相关。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（miRNAs）是一类小的非编码RNA，通过与信使RNA（mRNAs）3'端非翻译区部分互补的靶序列配对，促进mRNA降解和/或阻断mRNA翻译，从而负调控基因表达。最近的研究表明，许多循环血清miRNA的水平在患有各种肝脏疾病和病理学（包括HCC、HBV和肝硬化）的患者中升高。因此，血清miRNA代表了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在PSC进展和相关并发症中具有独特表达模式的血清miRNA标签的子集。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签名与肝脏中miRNA和靶基因表达的关系。我们将在一项具有适当把握度的研究中证实从患病肝脏释放的血清PSC miRNA生物标志物预测晚期PSC的灵敏度和特异性。拟议的研究是可行的，代表了开发用于PSC诊断和预后的临床用途的新生物标志物的两个关键步骤，并提供了一个独特的机会，以确定参与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.