Biological Basis of Phenotypes and Clinical Outcomes in Biliary Atresia

描述（由申请人提供）：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，由肝外胆管的纤维炎性阻塞引起。尽管几乎一致进展为终末期肝硬化，但不同的进展率和治疗反应表明存在基于疾病生物学的未识别表型。鉴于疾病的多因素发病机制，我们先前在实验性胆道闭锁中结合了基于患者的功能基因组学和机制研究，并发现了促炎免疫在疾病发病机制中的核心作用。在该应用的初步研究中，我们为入组BARC前瞻性观察性多中心研究和皮质类固醇试验的患者建立了一个包含临床、实验室、组织学和全基因组表达数据的胆道闭锁平台。该平台的初步分析确定了与组织学特征生物学相关并与临床结局相关的新型分子亚型。在这里，我们提出了这些研究的逻辑延续，总体目标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的调控网络，2）确定对抗炎治疗有利反应的转录预测因子，3）定义胆道闭锁中炎症基因调控的细胞机制。为了实现这些目标，我们将扩大胆道闭锁平台，为入组BARC前瞻性观察性研究和皮质类固醇试验的患者提供临床/实验室和基因表达数据。然后，我们将分析该平台，以验证新的“炎症”和“纤维化”亚型，并证明它们与临床病程或疾病进展的相关性。为了深入了解调节个体亚型的分子网络，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实验系统来研究特定网络如何调节疾病的发病机制。使用炎症标记，我们将确定它是否与皮质类固醇治疗的反应率增加有关。最后，我们将使用两种亚型患者的单核细胞，利用互补的体外系统来探索上皮损伤的细胞机制。总的来说，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，并根据患者的生物构成进行个性化治疗。公共卫生相关性：该项目研究胆道闭锁，这是儿童慢性肝病的最常见原因，也是美国儿科肝移植的主要指征。总体目标是确定疾病表型和临床结果的生物学基础。为了实现这一目标，我们将在诊断时检查肝脏基因表达谱，以确定新的疾病表型，临床结果的预测因子和疾病机制。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: This project studies biliary atresia, the most common cause of chronic liver disease in children and the leading indication for pediatric liver transplantation in the United States. The overall aim is to define the biological basis of disease phenotypes and clinical outcomes. To achieve this aim, we will examine the liver gene expression profile at the time of diagnosis to identify new disease phenotypes, predictors of clinical outcome, and mechanisms of disease.