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）： 该申请提出了对NIDDK-Biliary闭锁研究联盟（BARC）的辅助研究。胆道闭锁是可变表型的多因素疾病，是由于儿童肝外胆道系统的纤维炎性阻塞而产生的。尽管疾病的多因素性质，但我们在实验性胆道闭锁中将基于患者的功能基因组学和机理研究结合在一起，以发现疾病发病机理中促炎性免疫的核心作用。在初步研究中，我们还将功能基因组学应用于发现分子特征，这些分子特征在两种主要临床形式的胆道闭锁上高度鲜明。基于这些研究，我们提出了由BARC批准的基于患者的辅助研究，在该研究中，我们使用储存的肝组织，临床学特征在演讲中以及有关长期结果的前瞻性数据，以定义临床表型的分子基础以及儿童胆小胆汁抗体的可变临床临床结果的决定因素。对于这些实验，我们的总体假设是整合基因组学会产生新的分子表型，并预测胆道闭锁的长期结果。该假设将通过以下特定目的进行检验：1）确定已知临床形式的转录基础并发现胆道闭锁的新型分子亚型，2）定义了预测胆道闭锁结果的分子特征，以及3），以发现对抗炎性治疗的有利反应的转录预测指标。为了实现这些目标，我们将创建一个单个数据挖掘平台，该平台包含临床和组织学数据的关键要素，并在诊断时使用胆道闭锁的婴儿的肝脏以及在BARC前瞻性数据库研究和皮质类临床临床试验中参与的疾病的后期使用胆道闭锁的肝脏的关键要素。然后，我们将使用最先进的生物信息学方法来分析平台，以确定表型表达和疾病进展的分子基础，并确定预测对抗炎治疗反应的生物标志物。总的来说，提出的实验将创造前所未有的机会，以完善胆道闭锁的诊断，增加对调节疾病进展的生物学过程的理解，并根据预测反应的分子生物标志物个性化治疗。