Advancing our Understanding of Rare Pediatric Liver Diseases

增进我们对罕见小儿肝病的了解

• 批准号: 9552414
• 负责人: Kathleen Mary Loomes
• 金额: $ 11.76万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9552414
• 关键词: 2 year old; Adherence; Affect; Alagille Syndrome; Ancillary Study; Applications Grants; Bile Acids; Biliary Atresia; Caring; Cessation of life; Child; Childhood; Clinical; Clinical Data; Clinical Trials; Collaborations; Copy Number Polymorphism; Data; Data Coordinating Center; Databases; Development; Diagnosis; Disease; Disease Outcome; Ensure; Extrahepatic; Gene Proteins; Genes; Genetic; Genetic Screening; Genetic study; Genomics; Genotype; Goals; Individual; Investigation; Knowledge; Laboratories; Liver; Liver diseases; Manuscripts; Mitochondria; Molecular; Mutation; Mutation Analysis; Natural History; Observational Study; Outcome; Participant; Pathogenesis; Pathology; Patients; Pediatric Hospitals; Performance; Philadelphia; Procedures; Process; Progressive intrahepatic cholestasis; Proteomics; Protocols documentation; Recruitment Activity; Request for Applications; Research; Research Infrastructure; Research Proposals; Resources; Safety; Sampling; Serum; Serum Proteins; Services; Single Nucleotide Polymorphism; Technology; Testing; Time; U-Series Cooperative Agreements; United States National Institutes of Health; Variant; Work; biliary tract; biobank; cohort; dissemination research; experimental study; genetic analysis; genome wide association study; genomic data; improved; improved outcome; infancy; liver cystic fibrosis; liver transplantation; member; neonatal hepatitis; next generation sequencing; novel therapeutics; outcome forecast; outcome prediction; patient stratification; predict clinical outcome; prediction algorithm; protein biomarkers; proteomic signature; public health relevance; research data dissemination; response; success; translational study; treatment strategy

DESCRIPTION (provided by applicant): This proposal is in response to a request for applications for the Continuation of ChiLDReN, the Childhood Liver Disease Research Network. Over the past ten years, through a coordinated effort, investigations of eight cholestatic pediatri disorders have been advanced and we have established a robust database and biorepository for further research. Little is known about the pathogenesis, natural history, and optimal treatment strategies for the rare pediatric liver diseases investigated by ChiLDReN. We at The Children's Hospital of Philadelphia (CHOP) propose to continue to participate in this Consortium, and thereby advance the field through collaborative research. Only through collaboration can we improve the quality and efficiency of care provided to all individuals diagnosed with one of the diseases studied by this network. CHOP has been a highly productive member of ChiLDReN for the last 10 years. In this application, we propose to continue our participation in all aspects of the ChiLDReN consortium, including clinical trials, observational study protocols, dissemination of research findings and ancillary studies. We also propose to continue genetic screening of patients with Alagille Syndrome in the laboratory of Dr. Nancy Spinner. In addition, we have included a proposal for Genetics and Pathology services that we can offer to the Network. Biliary atresia (BA) is a progressive idiopathic, necroinflammatory disease of the extrahepatic biliary tree that presents in infancy, and accounts for 50% of all pediatric liver transplantations in the U.S. Currently there is no accurate way to predict outcome in children with BA at the time of diagnosis. A reliable algorithm for predicting clinical outcome would be valuable in defining prognosis and stratifying patients in clinical trials. In addition, improved understanding of the underlying molecular mechanisms would promote the development of novel therapies. In our scientific proposal, we will test the hypothesis that genomic and proteomic factors can predict outcome in BA. Using existing genotyping data from our group, we will conduct a genome wide association study of BA patients to identify significant single nucleotide polymorphisms and copy number variants that modify disease outcome. We will compare the variants detected in children with biliary atresia who survived with native liver beyond two years of age to those who did not. We also propose in depth studies to investigate the functional consequences of the variants identified in the GWAS. As a complementary strategy, we will use advanced proteomic technologies to identify serum proteins that predict clinical outcome in BA. Our study will leverage the extensive clinical and genomic data and biospecimens already collected by the ChiLDREN consortium to identify genetic modifiers and protein biomarkers that can predict outcome in this devastating disease. Our investigative team has the expertise and track record necessary to conduct these experiments. We anticipate that this work will contribute new knowledge about the biologic pathogenesis of BA and accelerate the pace of research into new treatments.

描述（由申请人提供）：本提案是为了响应儿童肝病研究网络 ChiLDReN 的申请请求。在过去的十年中，通过协调努力，对八种胆汁淤积性儿科疾病的研究取得了进展，我们已经建立了强大的数据库和生物样本库以供进一步研究。关于 ChiLDReN 研究的罕见儿童肝脏疾病的发病机制、自然史和最佳治疗策略知之甚少。我们费城儿童医院 (CHOP) 建议继续参与该联盟，从而通过合作研究推动该领域的发展。只有通过合作，我们才能提高向所有被诊断患有该网络研究的疾病之一的个人提供的护理的质量和效率。过去 10 年来，CHOP 一直是 ChiLDReN 中高效的成员。在此申请中，我们建议继续参与 ChiLDReN 联盟的各个方面，包括临床试验、观察性研究方案、研究结果的传播和辅助研究。我们还建议继续在 Nancy Spinner 博士的实验室对 Alagille 综合征患者进行基因筛查。此外，我们还提出了可以向网络提供的遗传学和病理学服务的提案。胆道闭锁 (BA) 是一种进行性特发性肝外胆管树坏死性炎症性疾病，出现于婴儿期，占美国所有儿科肝移植的 50%。目前，尚无准确的方法来预测 BA 儿童的预后。诊断时间。预测临床结果的可靠算法对于定义临床试验中的预后和对患者进行分层非常有价值。此外，提高对潜在分子机制的理解将促进新疗法的开发。在我们的科学提案中，我们将检验基因组和蛋白质组因素可以预测 BA 结果的假设。利用我们小组现有的基因分型数据，我们将对 BA 患者进行全基因组关联研究，以确定显着的单核苷酸多态性和改变疾病结果的拷贝数变异。我们将比较在两岁以上仍保留天然肝脏的胆道闭锁儿童中检测到的变异与未存活的儿童中检测到的变异。我们还建议进行深入研究，以调查 GWAS 中发现的变异的功能后果。作为补充策略，我们将使用先进的蛋白质组学技术来鉴定可预测 BA 临床结果的血清蛋白。我们的研究将利用 ChiLDREN 联盟已经收集的广泛临床和基因组数据以及生物样本来识别可以预测这种毁灭性疾病结果的基因修饰剂和蛋白质生物标志物。我们的研究团队拥有进行这些实验所需的专业知识和记录。我们预计这项工作将贡献有关 BA 生物学发病机制的新知识，并加快新疗法的研究步伐。