Molecular determinants of clinical phenotypes in biliary atresia

胆道闭锁临床表型的分子决定因素

• 批准号: 7345633
• 负责人: JORGE A. BEZERRA
• 金额: $ 27.09万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2008-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7345633
• 关键词: Adrenal Cortex Hormones; Ancillary Study; Anti-Inflammatory Agents; Anti-inflammatory; Arts; Biliary Atresia; Bioinformatics; Biological Markers; Biological Process; Child; Clinical; Clinical Trials; Data; Databases; Diagnosis; Disease; Disease Progression; Elements; Enrollment; Extrahepatic Bile Ducts; Gene Expression; Genome; Genomics; Immunity; Infant; Inflammatory; Liver; Methods; Molecular; Molecular Profiling; Nature; Obstruction; Outcome; Pathogenesis; Patients; Phase; Phenotype; Research; Role; Testing; Time; Tissues; base; clinical phenotype; data mining; functional genomics; novel; prospective; research study; response

DESCRIPTION (provided by applicant): This application proposes ancillary studies to the NIDDK-Biliary Atresia Research Consortium (BARC). Biliary atresia is a multifactorial disease of variable phenotypes that results from a fibro-inflammatory obstruction of the extrahepatic biliary system in children. Despite the multifactorial nature of disease, we combined patient-based functional genomics and mechanistic studies in experimental biliary atresia to discover a central role for proinflammatory immunity in disease pathogenesis. In preliminary studies, we also applied functional genomics to uncover molecular signatures that are highly distinctive of the two main clinical forms of biliary atresia. Based on these studies, we propose patient-based ancillary studies approved by BARC in which we use stored liver tissue, clinico-histological features at presentation, and prospective data on long-term outcome to define the molecular basis for clinical phenotypes and the determinants of the variable clinical outcomes of children biliary atresia. For these experiments, our overall hypothesis is that integrative genomics yields new molecular phenotypes and predicts long-term outcome in biliary atresia. This hypothesis will be tested by the following specific aims: 1) to determine the transcriptional basis of known clinical forms and discover novel molecular subtypes of biliary atresia, 2) to define molecular signatures that predict outcome of biliary atresia, and 3) to discover transcriptional predictors of favorable response to anti-inflammatory treatment. To achieve these aims, we will create a single data-mining platform that contains key elements of clinical and histological data combined with genome-wide levels of gene expression using livers of infants with biliary atresia at the time of diagnosis and at later phases of disease enrolled in the BARC prospective database study and corticosteroid clinical trial. We will then use state-of-the-art bioinformatics methods to analyze the platform to determine the molecular basis of phenotypic expression and of progression of disease, and to identify biomarkers that predict response to anti-inflammatory treatment. Collectively, the proposed experiments will create unprecedented opportunities to refine the diagnosis of biliary atresia, increase understanding of the biological processes regulating disease progression, and individualize treatment according to molecular biomarkers predictive of response.

描述（由申请人提供）： 本申请向 NIDDK-胆道闭锁研究联盟 (BARC) 提出了辅助研究。胆道闭锁是一种表型可变的多因素疾病，由儿童肝外胆道系统纤维炎症阻塞引起。尽管疾病具有多因素性质，但我们将基于患者的功能基因组学和实验性胆道闭锁的机制研究结合起来，发现促炎免疫在疾病发病机制中的核心作用。在初步研究中，我们还应用功能基因组学来揭示胆道闭锁两种主要临床形式的高度独特的分子特征。基于这些研究，我们提出了 BARC 批准的基于患者的辅助研究，其中我们使用储存的肝组织、临床组织学特征以及长期结果的前瞻性数据来定义临床表型的分子基础和决定因素儿童胆道闭锁的临床结果各不相同。对于这些实验，我们的总体假设是整合基因组学产生新的分子表型并预测胆道闭锁的长期结果。该假设将通过以下具体目标进行检验：1) 确定已知临床形式的转录基础并发现胆道闭锁的新分子亚型，2) 定义预测胆道闭锁结果的分子特征，3) 发现胆道闭锁的转录基础对抗炎治疗有良好反应的预测因子。为了实现这些目标，我们将创建一个单一的数据挖掘平台，其中包含临床和组织学数据的关键要素，以及使用胆道闭锁婴儿在诊断时和疾病后期阶段的肝脏进行的全基因组基因表达水平。参加了 BARC 前瞻性数据库研究和皮质类固醇临床试验。然后，我们将使用最先进的生物信息学方法来分析该平台，以确定表型表达和疾病进展的分子基础，并确定预测抗炎治疗反应的生物标志物。总的来说，所提出的实验将创造前所未有的机会来完善胆道闭锁的诊断，增加对调节疾病进展的生物过程的理解，并根据预测反应的分子生物标志物进行个体化治疗。