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

基本信息

批准号：
10824147
负责人：
JORGE A. BEZERRA
金额：
$ 48.39万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-10 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10824147
关键词：
Affect 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 Disease Disease Progression Duct (organ) structure Engineering Epithelium Extrahepatic Extrahepatic Bile Ducts Extrahepatic Cholestasis Fibrosis Foundations Gene Expression Profile Genes Glutathione Metabolism Pathway Goals Hepatic Hepatic Duct 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 Technology Testing Therapeutic Tissues United States Work bile duct biomarker identification cholangiocyte chronic liver disease clinical care clinical phenotype clinical practice clinically relevant cohort connectome cytokine design diagnostic accuracy diagnostic algorithm disease phenotype early childhood end stage liver disease epithelial injury experimental study fibrogenesis genetic signature improved infancy insight liver biopsy liver transplantation molecular phenotype mouse model new therapeutic target novel marker novel therapeutic intervention personalized care preclinical trial predict clinical outcome predictive signature prospective receptor repaired response segregation specific biomarkers synergism therapeutic target tissue injury tissue repair tool transcriptome transcriptome sequencing transcriptomics translational study

项目摘要

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.

项目概要/摘要这是一项竞争性更新应用，研究临床表型和结果的生物学基础胆道闭锁，新生儿胆汁淤积的最常见原因。该疾病是由纤维炎症引起的肝外胆管阻塞并出现在婴儿早期。尽管进展几乎一致，但最终肝硬化阶段，对手术/药物治疗的不同反应以及疾病进展速度表明存在未识别的生物过程，这些过程正在驱动不同的表型或疾病阶段。在该奖项的上一届任期中，我们发现了通过 IL-8、TNF 和成分增强信号传导的证据炎症小体在胆管损伤发病机制中的作用以及分子回路的同时激活依赖IL-33来诱导组织修复。我们还确定了 MMP-7 在胆管上皮损伤中的关键作用并作为胆道闭锁的高度敏感和特异性的生物标志物。为了准备这个应用程序，我们应用计算机建模和高级分析来挖掘肝脏转录组，发现了一个 14 基因预测天然肝脏 2 年存活率的签名，并将谷胱甘肽代谢确定为新的抑制纤维化的治疗目标。使用血清蛋白质组学，我们还发现了血清蛋白与门脉高压确定的晚期纤维化儿童隔离。这些数据形成为三个相互关联的目标提出的新研究奠定了基础：1）发现分子决定因素胆道闭锁的结果和发病机制，2）确定门静脉高压症的生物标志物肝脏疾病的进展，以及 3) 确定胆道闭锁组织损伤的致病机制。目标 1 的实验将使用来自大型队列的 RNAseq 数据来挖掘基因组和分子途径预测临床结果，然后对胆道闭锁小鼠模型进行补充研究临床前试验中的新生儿纤维化通过靶向肝脏代谢回路来抑制纤维化。实验 for Aim 2 将使用血清蛋白质组学数据来研究 SEMA6B、sFRP3、COMMD7、VCAM1 和 BMX 如何单独或组合作为门静脉高压症的生物标志物。目标 3 中的实验将从胆道闭锁受试者的肝脏中提取胆道类器官，并检验与胆道类器官缺陷相关的假设细胞成熟以及胆管细胞纤维生成的激活如何成为胆汁的重要机制导管损伤。通过应用高度互补的方法来研究来自足够规模的队列的组织已经进行了前瞻性的表型分析，我们的实验将提供对疾病的新生物标志物的见解，它们的在发病机制中的作用，以及如何根据生物学终点个性化新的临床试验。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Diagnostic Accuracy of Serum Matrix Metalloproteinase-7 for Biliary Atresia.

血清基质金属蛋白酶 7 对胆道闭锁的诊断准确性。

DOI：
发表时间：
2018-12
期刊：
影响因子：
0
作者：
Yang, Li;Zhou, Ying;Xu, Pei;Mourya, Reena;Lei, Hai;Cao, Guo;Xiong, Xiao;Xu, Hui;Duan, Xu;Wang, Na;Fei, Lin;Chang, Xiao;Zhang, Xi;Jiang, Meng;Bezerra, Jorge A;Tang, Shao
通讯作者：
Tang, Shao

Biliary atresia in Brazil: where we are and where we are going.

巴西的胆道闭锁：我们现在在哪里，我们要去哪里。