Biological Basis of Phenotypes and Clinical Outcomes in Biliary Atresia

项目概要/摘要 本申请向NIDDK-胆道闭锁研究联盟（BARC）提出了辅助研究。 胆道闭锁是新生儿胆汁淤积症最常见的原因， 肝外胆管尽管进展到终末期肝硬化几乎是一致的， 进展和对治疗的反应表明存在未识别的表型，这些表型基于 疾病的生物学鉴于疾病的多因素发病机制，我们先前将患者- 基于实验性胆道闭锁的功能基因组学和机制研究， 促炎免疫在疾病发病机制中的作用。在此应用程序的初步研究中，我们构建了一个 胆道闭锁平台，包含临床、实验室、组织学和全基因组表达数据， 入组BARC前瞻性观察性多中心研究和皮质类固醇试验的患者。初始 对该平台的分析鉴定出与组织学特征生物学相关的新分子亚型 并与临床结果相关。在这里，我们提出了这些研究的逻辑延续， 目的是确定胆道闭锁儿童疾病表型和临床结局的生物学基础。 为此，我们将追求三个目标：1）发现胆道闭锁的新分子亚型，并定义 关键调控网络，2）确定对抗炎反应有利的转录预测因子 明确胆道闭锁炎症基因调控的细胞机制。到 实现这些目标，我们将扩大胆道闭锁平台的临床/实验室和基因表达 入组BARC前瞻性观察性研究和皮质类固醇试验的患者数据。然后我们将 分析该平台，以验证新的“炎症”和“纤维化”亚型，并证明其 与临床病程或疾病进展相关。为了深入了解分子网络调节 个别亚型，我们将应用功能和比较基因组学，并使用基于细胞和器官的 研究特定网络如何调节疾病发病机制的实验系统。使用 炎症标志，我们将确定它是否与增加的反应率有关， 皮质类固醇治疗。最后，我们将使用互补的体外系统来探索细胞机制， 使用来自具有两种亚型的患者的单核细胞的上皮损伤。总体而言，拟议的 实验将创造前所未有的机会，重新定义疾病的临床谱， 根据患者的生物学构成进行个性化治疗。

PROJECT SUMMARY/ABSTRACT This application proposes ancillary studies to the NIDDK-Biliary Atresia Research Consortium (BARC). Biliary atresia, the most common cause of neonatal cholestasis, results from a fibro-inflammatory obstruction of extrahepatic bile ducts. Despite nearly uniform progression to end-stage cirrhosis, the variable rate of progression and response to treatment suggest the existence of unrecognized phenotypes that are based on the biology of disease. In view of the multifactorial pathogenesis of disease, we previously combined patient- based functional genomics and mechanistic studies in experimental biliary atresia and discovered a central role for proinflammatory immunity in disease pathogenesis. In preliminary studies for this application, we built a biliary atresia platform containing clinical, laboratory, histological, and genome-wide expression data for patients enrolled in a BARC prospective observational multi-center study and a corticosteroid trial. Initial analysis of this platform identified novel molecular subtypes that are biologically linked to histological features and relevant to the clinical outcome. Here, we propose a logical continuation of these studies with the overall aim of defining the biological basis for disease phenotypes and clinical outcomes of children with biliary atresia. To this end, we will pursue three aims: 1) To discover novel molecular subtypes of biliary atresia and define key regulatory networks, 2) To determine transcriptional predictors of favorable response to anti-inflammatory treatment, and 3) To define the cellular mechanisms regulated by inflammatory genes in biliary atresia. To achieve these aims, we will expand the biliary atresia platform with clinical/laboratory and gene expression data for patients enrolled in the BARC prospective observational study and the corticosteroid trial. We will then analyze the platform to validate the novel "inflammatory" and "fibrosing" subtypes and demonstrate their relevance to clinical course or progression of disease. To obtain insight into molecular networks regulating individual subtypes, we will apply functional and comparative genomics and use cell- and organ-based experimental systems to investigate how specific networks regulate pathogenesis of disease. Using the inflammatory signature, we will determine whether it is associated with an increased response rate to corticosteroid treatment. Finally, we will use complementary in vitro systems to explore cellular mechanisms of epithelial injury using mononuclear cells from patients with both subtypes. Collectively, the proposed experiments will create unparalleled opportunities to re-define the clinical spectrum of disease and to individualize treatments according to the patients' biological makeup.