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: 10201576
• 负责人: JORGE A. BEZERRA
• 金额: $ 50.72万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201576
• 关键词: Affect; Algorithms; Animal Model; Automobile Driving; Award; BMX gene; Bile Duct Epithelium; Biliary; Biliary Atresia; Biological; Biological Markers; Biological Process; Cell Maturation; Cell Survival; Cells; Child; Childhood; Cholestasis; Cirrhosis; Clinical; Clinical Course of Disease; Clinical Data; Clinical Trials; Computer Models; Data; Data Analytics; Defect; Diagnosis; Diagnostic; Disease; Disease Progression; Duct (organ) structure; Engineering; Epithelial; Extrahepatic; Extrahepatic Bile Ducts; Extrahepatic Cholestasis; Fibrosis; Foundations; Gene Expression Profile; Genes; Glutathione Metabolism Pathway; Goals; Hepatic; Human; IL8 gene; Immune; Individual; Inflammasome; Inflammatory; Injury; Interleukin-13; Investigation; Knowledge; Life; Liver; Liver diseases; Matrilysin; Medical; Metabolic; Molecular; Molecular Profiling; Monitor; Neonatal; Obstruction; Operative Surgical Procedures; Organoids; Outcome; Paper; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phenotype; Play; Portal Hypertension; Positioning Attribute; Predisposition; Preparation; Property; Proteome; Proteomics; Protocols documentation; Publishing; Reporting; Role; Sentinel; Serum; Serum Proteins; Signal Transduction; Staging; Subgroup; Surveys; TNF gene; TNFRSF1B gene; Technology; Testing; Therapeutic; Tissues; United States; Work; base; bile duct; cholangiocyte; chronic liver disease; clinical care; clinical phenotype; clinical practice; clinically relevant; cohort; connectome; cytokine; design; diagnostic accuracy; disease phenotype; early childhood; epithelial injury; experimental study; fibrogenesis; genetic signature; improved; infancy; insight; liver biopsy; liver transplantation; molecular phenotype; mouse model; new therapeutic target; novel marker; personalized care; preclinical trial; predict clinical outcome; predictive signature; prospective; receptor; repaired; response; specific biomarkers; synergism; therapeutic target; tissue injury; tissue repair; tool; transcriptome; transcriptome sequencing; transcriptomics; translational study

PROJECT SUMMARY/ABSTRACT This is a competing renewal application studying the biological basis of clinical phenotype and outcome of biliary atresia, the most common cause of neonatal cholestasis. The disease results from a fibro-inflammatory obstruction of extrahepatic bile ducts and present in early infancy. Despite nearly uniform progression to end- stage cirrhosis, the variable response to surgical/medical treatment and rate of progression of disease suggest the existence of unrecognized biological processes that are driving different phenotypes or stages of disease. In the previous tenure of the award, we found evidence of increased signaling via IL-8, TNF, and components of the inflammasome in pathogenesis of bile duct injury, and the simultaneous activation of molecular circuits dependent on IL-33 to induce tissue repair. We also identified a key role for MMP-7 in bile duct epithelial injury and as a highly sensitive and specific biomarker for biliary atresia. In preparation for this application, we applied computer modeling and high analytics to mine the hepatic transcriptome and found a 14-gene signature that predicts 2-year survival with the native liver and identifies glutathione metabolism as a new therapeutic target to suppress fibrosis. Using serum proteomics, we also uncovered serum proteins that segregate with children with advanced fibrosis as determined by portal hypertension. These data form the foundation for the new studies proposed in three inter-related aims: 1) To discover molecular determinants of outcome and pathogenesis of biliary atresia, 2) To identify biomarkers of portal hypertension during progression of liver disease, and 3) To define pathogenic mechanisms of tissue injury in biliary atresia. Experiments for Aim 1 will use RNAseq data from a large cohort to mine gene groups and molecular pathways that predict clinical outcome, followed by complementary studies in mouse models of biliary atresia and neonatal fibrosis in pre-clinical trials to suppress fibrosis by targeting metabolic circuits in the liver. Experiments for Aim 2 will use data from serum proteomics to investigate how SEMA6B, sFRP3, COMMD7, VCAM1, and BMX perform as biomarkers of portal hypertension individually or in combination. And experiments in Aim 3 will derive biliary organoids from the liver of subjects with biliary atresia and test hypothesis related to defects of cell maturation and to how the activation of fibrogenesis in cholangiocytes is an important mechanisms of bile duct injury. By applying highly complementary approaches to study tissues from adequately sized cohorts that have been phenotyped prospectively, our experiments will provide insight into new biomarkers of disease, their role in pathogenesis, and how new clinical trials can be personalized based on biological end-point.

项目摘要/摘要 这是研究临床表型的生物学基础和结果 胆道闭锁，是新生儿胆汁淤积的最常见原因。该疾病是由纤维炎症的 肝外胆管的阻塞，并在婴儿早期出现。尽管几乎均匀地发展到结束 肝硬化，对手术/医学治疗和疾病进展的可变反应表明 驱动不同表型或疾病阶段的未识别生物学过程的存在。 在奖励的上一个任期中，我们发现了通过IL-8，TNF和组件增加信号传导的证据 胆管损伤发病机理中的炎症体，并同时激活分子电路 取决于IL-33诱导组织修复。我们还确定了MMP-7在胆管上皮损伤中的关键作用 作为胆道闭锁的高度敏感和特异性的生物标志物。为了准备此应用程序，我们 应用计算机建模和高分分析，以挖掘肝转录组并找到14基因 签名预测与天然肝的2年生存并确定谷胱甘肽代谢为一种新的 抑制纤维化的治疗靶标。使用血清蛋白质组学，我们还发现了血清蛋白 通过门户高血压确定的晚期纤维化儿童分离。这些数据形成 在三个相互关联的目的中提出的新研究基础：1）发现分子决定因素 胆道闭锁的结局和发病机理，2）确定门户高血压的生物标志物 肝病的进展和3）定义胆道闭锁的组织损伤的致病机制。 AIM 1的实验将使用来自大型队列的RNASEQ数据到地雷基因组和分子途径 这可以预测临床结果，然后在胆道闭锁的小鼠模型和 临床前试验中的新生儿纤维化，通过靶向肝脏中的代谢回路来抑制纤维化。实验 对于AIM 2，将使用来自血清蛋白质组学的数据来研究SEMA6B，SFRP3，COMMD7，VCAM1和BMX如何 单独或组合作为门户高血压的生物标志物。 AIM 3中的实验将 从患有胆道闭锁的受试者的肝脏中得出胆道类器官，并与与缺陷有关的假设 细胞成熟以及胆管细胞中纤维发生的激活如何是胆汁的重要机制 管道损伤。通过应用高度互补的方法来研究来自适当大小的队列的组织 已经被前瞻性地表现出来，我们的实验将提供对新的疾病生物标志物的见解 在发病机理中的作用，以及如何基于生物学终点来个性化新的临床试验。