Circulating miRNA as a biomarker for biliary atresia

描述（由申请人提供）：胆道闭锁（BA）是一种婴儿疾病，其中胆管被逐渐破坏（综述见（7））。如果不治疗，疾病统一进展为胆汁性肝硬化，肝功能衰竭，并在2年内死亡。的初始治疗 胆道闭锁是肝门肠吻合术，其中切除胆道残余物，并将空肠的Roux-en-Y分支放置在肝门处与暴露的肝表面邻接。这在约50%的病例中是成功的（8-11），但即使是明显充分的胆道引流的患者也可能发生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。因此，胆道闭锁是美国小儿肝移植最常见的适应症。由于不能将其与新生儿生理性黄疸区分开来，诊断常常被延误。相反，黄疸婴儿的诊断检查是广泛的，包括血液检查，超声检查，核医学扫描，肝活检和术中胆管造影。对BA进行敏感的非侵入性检测可以加速诊断，同时也可以避免没有BA的儿童进行不必要的侵入性检测。循环microRNA是一种新的生物标志物，在BA中从未被探索过。该提案中提出的初步数据表明，与其他原因引起黄疸的儿童相比，BA婴儿的循环microRNA特别升高。因此，本提案的目的1旨在验证microRNA作为诊断BA的非侵入性生物标志物的用途。BA患儿治疗的另一个挑战是肝门肠吻合术后的预后预测。如果儿童可以在这些结果的发展之前被识别出来，就可以提供更积极的监测、营养、预期咨询--也许在未来，还可以提供治疗。因此，该提案的目的2集中于测试循环miRNA预测肝门肠吻合术后天然肝脏存活的能力。成功实施基于miRNA的非侵入性BA诊断和预后测试有望对患有该疾病的儿童产生直接和重大的影响。它也可能导致有关BA发病机制和进展的见解，以及在其他肝脏疾病中的应用。 公共卫生相关性：胆道闭锁（BA）是一种婴儿疾病，其中连接肝脏和肠道的胆管被破坏。这是一个孩子最常见的原因， 需要在美国进行肝脏移植。该提案的目标是开发新的BA非侵入性诊断和预后测试，以便儿童能够尽早诊断并接受治疗，因为这对是否需要肝移植有重大影响。

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. PUBLIC HEALTH RELEVANCE: Biliary atresia (BA) is a disease of infants in which the bile ducts linking the liver to the intestine are destroyed. It is the most common reason for a child to need a liver transplant in the US. The goal of this proposal is to develop new non-invasive diagnostic and prognostic tests for BA, so that children can be diagnosed and receive treatment as early as possible, because this has a major effect on whether or not liver transplant will be necessary.