Biological Basis of Phenotypes and Clinical Outcomes in Biliary Atresia

项目摘要/摘要 该申请建议对NIDDK-胆道闭锁研究联盟(BARC)进行辅助研究。 胆道闭锁是新生儿胆汁淤积症最常见的原因，由纤维炎性梗阻引起 肝外胆管。尽管进展几乎一致到终末期肝硬化，但可变率 进展和对治疗的反应表明存在未被识别的表型，其基础是 疾病的生物学。鉴于疾病的多因素发病机制，我们先前结合了患者- 基于功能基因组学和机制研究的实验性胆道闭锁 促炎症免疫在疾病发病机制中的作用。在这个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 患者参加了BARC前瞻性多中心观察性研究和皮质类固醇试验。首字母 对该平台的分析确定了在生物学上与组织学特征相关的新的分子亚型 并与临床结果相关。在这里，我们建议将这些研究的逻辑延续到总体上 目的明确儿童胆道闭锁的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，并确定 关键调控网络，2)确定抗炎反应有利的转录预测因子 3)明确炎症基因调控胆道闭锁的细胞机制。至 为了达到这些目标，我们将扩大胆道闭锁的临床/实验室和基因表达平台 参加BARC前瞻性观察研究和皮质类固醇试验的患者的数据。到时候我们会的 分析平台以验证新的“炎症性”和“纤维化”亚型，并展示其 与临床病程或疾病进展有关。深入了解分子网络调节 个别亚型，我们将应用功能基因组学和比较基因组学，并使用基于细胞和器官的 研究特定网络如何调控疾病发病机制的实验系统。使用 炎性特征，我们将确定它是否与增加的应答率有关 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 使用来自两种亚型患者的单个核细胞进行上皮损伤。总的来说，建议的 实验将创造无与伦比的机会，重新定义疾病的临床谱系，并 根据患者的生物构成进行个体化治疗。

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.