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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.

项目总结/文摘

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.

DOI：
10.1002/hep.30234
发表时间：
2018-12
期刊：
Hepatology (Baltimore, Md.)
影响因子：
0
作者：
Yang L;Zhou Y;Xu PP;Mourya R;Lei HY;Cao GQ;Xiong XL;Xu H;Duan XF;Wang N;Fei L;Chang XP;Zhang X;Jiang M;Bezerra JA;Tang ST
通讯作者：
Tang ST

Advances in biliary atresia: from patient care to research.

胆道闭锁的进展：从患者护理到研究。