Circulating miRNA as a biomarker for biliary atresia

描述(由申请人提供)：胆道闭锁(BA)是一种婴儿的疾病，其中胆管逐渐被破坏(回顾(7))。如果不治疗，这种疾病会统一发展为胆汁性肝硬化、肝功能衰竭，并在两年内死亡。本病的初步治疗 胆道闭锁是一种肝门肠吻合术，切除胆道残端，在肝门处放置空肠Roux-en-Y分支与裸露的肝脏表面相连。成功率约为50%(8-11例)，但即使胆道引流明显充足的患者也可能出现持续的肝纤维化和胆管丢失。最终，大多数胆道闭锁患者将需要肝移植。S因此，胆道闭锁是美国儿童肝移植最常见的适应症，由于未能将疾病与生理性新生儿黄疸区分开来，诊断往往被延误。相反，黄褐症婴儿的诊断工作是广泛的，包括血液检查、超声检查、核医学扫描、肝脏活检和术中胆道造影。对BA实施敏感的非侵入性检测可以加快诊断速度，同时也可以省去没有BA的儿童不必要的侵入性检测。循环microRNA是一类新的生物标志物，在BA中从未被探索过。这项建议中提出的初步数据表明，与其他原因引起的黄疸儿童相比，患有BA的婴儿循环中的microRNAs特异性升高。因此，本提案的目的1旨在验证microRNAs作为诊断BA的非侵入性生物标记物的使用。治疗BA儿童的另一个挑战是预测肝门肠吻合术后的结果。如果能够在出现这些结果之前确定儿童的身份，就可以提供更积极的监测、营养、前瞻性咨询--也许在未来，还可以提供治疗。因此，该提案的目标2侧重于测试循环miRNA预测肝门肠吻合术后与自然肝脏存活的能力。对BA成功实施基于miRNA的非侵入性诊断和预后测试有望对患有这种疾病的儿童产生直接和重大的影响。这也可能导致对BA的发病机制和进展的深入了解，以及在其他肝病中的应用。

DESCRIPTION (provided by applicant): Biliary atresia (BA) is a disease of infants in which the bile ducts are progressively destroyed (reviewed in (7)). If untreated, the disease uniformly progresses to biliary cirrhosis, liver failure, and death within 2 years. The initial treatment for biliary atresia is the hepato-portoenterostomy procedure, in which the biliary remnants are excised and a Roux-en-Y limb of jejunum is placed in contiguity with the exposed liver surface at the porta hepatis. This is successful in ~50% of cases (8-11), but even patients with apparently adequate biliary drainage may experience ongoing hepatic fibrosis and bile duct loss. Ultimately the majority of patients with biliary atresia will require liver transplantation. s a result, biliary atresia is the most common indication for pediatric liver transplantation in the US The diagnosis is often delayed due to a failure to distinguish the disease from physiologic neonatal jaundice. Conversely, the diagnostic work-up of the jaundiced infant is extensive, including blood tests, ultrasonography, nuclear medicine scans, liver biopsy, and intra-operative cholangiogram. The implementation of a sensitive non-invasive test for BA could accelerate the diagnosis, while also sparing children without BA unnecessary and invasive testing. Circulating microRNA is a novel category of biomarker that has never been explored in BA. The preliminary data presented in this proposal demonstrate that circulating microRNAs are specifically elevated in infants with BA in comparison to children with jaundice from other causes. Aim 1 of this proposal therefore aims to validate the use of microRNAs as non-invasive biomarkers for the diagnosis of BA. Another challenge in the care of children with BA is the prediction of outcome after hepato- portoenterostomy. If children can be identified prior to the development of these outcomes, more aggressive monitoring, nutrition, anticipatory counseling - and perhaps in the future, therapy - can be provided. Aim 2 of the proposal therefore focuses on testing the ability of circulating miRNA to predict survival with the native liver after hepato-portoenterostomy. The successful implementation of miRNA-based, non-invasive diagnostic and prognostic tests for BA promises to have an immediate and significant impact on children with the disease. It may also lead to insights regarding BA pathogenesis and progress, as well as applications in other liver diseases.