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: 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
• 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

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）：这是对NIDDK-Childhood-Childhood肝病研究和教育网络（儿童）提出辅助研究的竞争更新申请。胆道闭锁是新生儿胆汁淤积的最常见原因，是由于肝外胆管的纤维炎性阻塞引起的。尽管几乎均匀地向末期肝硬化进展，但对手术/医疗治疗和疾病进展率的可变反应表明，存在驱动不同表型或疾病阶段的未识别的生物学过程。在该奖项的第一个任期中，我们在病原机制中发现了树突状和天然杀伤细胞的证据，确定了ADD3基因在疾病易感性中的作用，并在表现时产生了肝病的炎症和纤维化阶段的基因表达特征，即使在这些阶段没有使用这些阶段的临床结果中，也没有使用这些阶段的临床效果。在此应用的发现类型的初步研究中，我们量化了血清中的炎症生物标志物，并鉴定出对胆道闭锁高度特异的蛋白质谱，并预测对手术治疗的适当反应。这些数据构成了与胆道损伤发病机理相关的肝和循环生物标志物的总体假设的基础，这是诊断，肝病阶段和临床结果的预测指标。为了检验这一假设，我们 将创建一个具有关键临床，实验室和组织学数据的数据集成平台，并结合胆道闭锁和患病和健康控制的患者的基因（肝脏）和蛋白质（在血清中）的全面表达曲线。我们将挖掘实现三个目标的平台：1）定义疾病阶段，以诊断胆道闭锁，与临床结果相关，2）确定生物学预测因子和对治疗的有利反应，以及3）发现组织纤维化的血清生物标志物和cirrhhosis的临床终点。 AIM 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，并在诊断时分期肝病，确定对类固醇治疗的反应的分子预测指标，并研究新的疾病转录机制。目标2和3的实验将使用蛋白质 - 培训技术来量化炎症和纤维化的血清生物标志物以及高度严格的统计模型，以根据患者的生物构成（疾病阶段）来定义先前未被认可的患者亚组，这些疾病阶段可以预测对标准手术，新医疗治疗，新医疗治疗和港口型端口的反应。通过将高度互补的方法应用于从儿童前瞻性表型的足够大小的同类群体中研究组织，我们的实验将洞悉未来的临床试验和受影响儿童的护理，以基于疾病的生物标志物进行个性化化。