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：
8818246
负责人：
JORGE A. BEZERRA
金额：
$ 45.19万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8818246
关键词：
Accounting Affect Algorithms Ancillary Study Automobile Driving Award Biliary Biliary Atresia Biochemical Biological Biological Markers Biological Process Biology Caring Cells Child Childhood Cholestasis Cirrhosis Clinical Clinical Research Clinical Trials Data Data Set Dendritic Cells Diagnosis Diagnostic Disease Disease Progression Disease susceptibility Education Extrahepatic Cholestasis Fibrosis Foundations Future Gene Expression Profile Genes Genetic Predisposition to Disease Genome Goals Health Hepatic Histologic Immune Immune system Inflammation Inflammatory Injury Intrahepatic bile duct Investigation Laboratories Link Liver Liver diseases Medical Mining Modeling Molecular Molecular Profiling Monitor National Institute of Diabetes and Digestive and Kidney Diseases Natural Killer Cells Neonatal Operative Surgical Procedures Outcome Pathogenesis Patients Phenotype Portal Hypertension Positioning Attribute Proteins Protocols documentation Publications Reporting Research Research Infrastructure Role Serum Serum Proteins Signal Transduction Specificity Stage at Diagnosis Staging Statistical Models Steroids Subgroup Technology Testing Therapeutic Tissue-Specific Gene Expression Tissues United States Work base chronic liver disease clinical phenotype cohort cytokine cytotoxicity data integration design disease phenotype early childhood improved insight liver transplantation overexpression promoter protein profiling research study response treatment response

项目摘要

DESCRIPTION (provided by applicant): This is a competing renewal application proposing ancillary studies to the NIDDK-Childhood Liver Disease Research and Education Network (ChiLDREN). 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 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 first tenure of the award, we found evidence for dendritic and natural killer cells in pathogenic mechanisms of disease, identified a role for the ADD3 gene in susceptibility of disease, and generated a gene expression signature of inflammatory and fibrotic stages of liver disease at presentation, which have relationship to clinical outcome even when these stages are not present using standard histological criteria. In discovery-type preliminary studies for this application, we quantified inflammatory biomarkers in the serum and identified protein profiles that are highly specific for biliary atresia and predict adequate response to surgical treatment. These data form the foundation for the overall hypothesis that hepatic and circulating biomarkers linked to pathogenesis of biliary injury are predictors of diagnosis, stages of liver disease, and clinical outcome. To test this hypothesis, we will create a Data Integration Platform with key clinical, laboratory and histological data combined with comprehensive expression profiles for genes (in the liver) and protein (in the serum) of patients with biliary atresia and diseased- and healthy-controls. We will mine the platform to pursue three aims: 1) To define disease stages at diagnosis of biliary atresia with relevance to clinical outcome, 2) To identify biological predictors and favorable response to treatment, and 3) To discover serum biomarkers of tissue fibrosis and clinical end-points of cirrhosis. Experiments for Aim 1 will use RNAseq to generate whole-genome expression datasets to validate inflammatory and fibrotic signatures and stage the liver disease at diagnosis, identify molecular predictors of response to steroid treatment, and investigate new transcriptional mechanisms of disease. Experiments for Aims 2 and 3 will use protein-multiplexing technologies to quantify serum biomarkers of inflammation and fibrosis and highly stringent statistical models to define previously unrecognized subgroups of patients based on their biological makeup (stages of disease) that are predictive of response to standard surgery, new medical therapies, and progression of portal hypertension. By applying highly complementary approaches to study tissues from adequately sized cohorts that have been prospectively phenotyped by ChiLDREN, our experiments will provide insight into how future clinical trials and the care of affected children can be personalized based on biomarkers of disease.

描述（由申请人提供）：这是一项竞争性更新申请，提议对 NIDDK 儿童肝病研究和教育网络 (ChiLDREN) 进行辅助研究。胆道闭锁是新生儿胆汁淤积的最常见原因，是由肝外胆管的纤维炎症阻塞引起的。尽管进展为终末期肝硬化几乎一致，但对手术/药物治疗的不同反应和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。在该奖项的第一个任期内，我们发现了树突状细胞和自然杀伤细胞在疾病致病机制中的证据，确定了 ADD3 基因在疾病易感性中的作用，并生成了肝病炎症和纤维化阶段的基因表达特征表现，即使使用标准组织学标准不存在这些阶段，也与临床结果相关。在该应用的发现型初步研究中，我们量化了血清中的炎症生物标志物，并鉴定了对胆道闭锁高度特异性的蛋白质谱，并预测对手术治疗的充分反应。这些数据构成了总体假设的基础，即与胆道损伤发病机制相关的肝脏和循环生物标志物是诊断、肝病阶段和临床结果的预测因素。为了检验这个假设，我们将创建一个数据集成平台，其中包含胆道闭锁患者以及患病和健康对照的关键临床、实验室和组织学数据，以及基因（肝脏中）和蛋白质（血清中）的综合表达谱。我们将利用该平台来实现三个目标：1）确定胆道闭锁诊断时与临床结果相关的疾病阶段，2）确定生物学预测因子和对治疗的有利反应，3）发现组织纤维化和胆道闭锁的血清生物标志物。肝硬化的临床终点。目标 1 的实验将使用 RNAseq 生成全基因组表达数据集，以验证炎症和纤维化特征，并在诊断时对肝脏疾病进行分期，识别类固醇治疗反应的分子预测因子，并研究疾病的新转录机制。目标 2 和 3 的实验将使用蛋白质多重技术来量化炎症和纤维化的血清生物标志物，并使用高度严格的统计模型来根据患者的生物组成（疾病阶段）来定义以前未识别的患者亚组，这些生物组成可预测对标准手术的反应、新的药物疗法以及门静脉高压症的进展。通过应用高度互补的方法来研究 ChiLDREN 前瞻性表型的足够大小的队列中的组织，我们的实验将深入了解如何根据疾病的生物标志物对未来的临床试验和受影响儿童的护理进行个性化。