Biological Basis of Phenotypes and Clinical Outcomes in Biliary Atresia

胆道闭锁表型和临床结果的生物学基础

• 批准号: 8321581
• 负责人: JORGE A. BEZERRA
• 金额: $ 31.98万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8321581
• 关键词: Adrenal Cortex Hormones; Ancillary Study; Anti-Inflammatory Agents; Anti-inflammatory; Biliary Atresia; Bioinformatics; Biological; Biological Assay; Biological Process; Biology; CD8B1 gene; Cells; Cellular biology; Child; Childhood; Cholestasis; Cirrhosis; Clinical; Clinical Data; Clinical Research; Cytolysis; Data; Diagnosis; Disease; Disease Progression; Enrollment; Epithelial; Extrahepatic Cholestasis; Fibrosis; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Grant; Hepatic; Human; Immunity; In Vitro; Individual; Infant; Inflammatory; Injury; Interferons; Laboratories; Link; Liver; Lymphocyte; Measures; Methods; Mining; Molecular; Molecular Profiling; Mononuclear; National Institute of Diabetes and Digestive and Kidney Diseases; Natural Killer Cells; Neonatal; Observational Study; Organ; Outcome; Pathogenesis; Patients; Phase; Phenotype; Research; Role; Signal Transduction; Staging; System; Testing; Therapeutic; Time; Tissues; United States; Variant; base; cholangiocyte; chronic liver disease; clinical phenotype; comparative genomics; data mining; disease phenotype; disorder subtype; early childhood; functional genomics; genome-wide; in vivo; insight; liver transplantation; mouse model; novel; prevent; programs; prospective; randomized placebo controlled trial; research study; response

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.

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的最常见原因，是由纤维炎症性阻塞引起的 肝外胆管。尽管进展为终末期肝硬化几乎一致，但不同程度的进展率 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。鉴于疾病的发病机制是多因素的，我们之前将患者与 基于实验性胆道闭锁的功能基因组学和机制研究，发现了一个中枢 促炎免疫在疾病发病机制中的作用。在此应用的初步研究中，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 前瞻性观察性多中心研究和皮质类固醇试验。最初的 该平台的分析确定了与组织学特征有生物学联系的新分子亚型 并与临床结果相关。在这里，我们提出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果的生物学基础。 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) 确定抗炎药物良好反应的转录预测因子 治疗，3) 明确胆道闭锁中炎症基因调节的细胞机制。到 为了实现这些目标，我们将通过临床/实验室和基因表达来扩展胆道闭锁平台 参加 BARC 前瞻性观察研究和皮质类固醇试验的患者数据。我们随后将 分析平台以验证新的“炎症”和“纤维化”亚型并证明其 与临床病程或疾病进展的相关性。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 炎症特征，我们将确定它是否与增加的反应率相关 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核细胞进行上皮损伤。总的来说，拟议的 实验将为重新定义疾病的临床谱和 根据患者的生物组成进行个体化治疗。