Advancing our Understanding of Rare Pediatric Liver Diseases

描述（由申请人提供）：本提案是针对儿童肝病研究网络继续儿童的申请请求而提出的。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调查已经取得进展，我们已经建立了一个强大的数据库和生物储存库，以供进一步研究。儿童调查的罕见儿童肝脏疾病的发病机制，自然历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进该领域。只有通过合作，我们才能提高向所有被诊断患有该网络所研究的一种疾病的个人提供护理的质量和效率。在过去的10年里，CHOP一直是儿童协会的高效成员。在本次申请中，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。我们还建议在南希·斯宾纳博士的实验室继续对阿拉吉尔综合征患者进行遗传筛查。此外，我们还提出了一项我们可以向网络提供的遗传学和病理学服务的建议。胆道闭锁（Biliary闭锁，BA）是一种进行性特发性肝外胆道树坏死性炎症性疾病，出现于婴儿期，占美国所有儿童肝移植的50%。目前尚无准确的方法来预测BA患儿的诊断结果。一种可靠的预测临床结果的算法将对临床试验中确定预后和患者分层有价值。此外，提高对潜在分子机制的理解将促进新疗法的发展。在我们的科学提案中，我们将检验基因组和蛋白质组学因素可以预测BA预后的假设。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，以确定影响疾病结局的显著单核苷酸多态性和拷贝数变异。我们将比较在胆道闭锁儿童中检测到的变异，这些儿童在两岁以上的天然肝脏存活下来，而那些没有。我们还建议进行深入的研究，以调查在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预测BA临床结果的血清蛋白。我们的研究将利用儿童联盟已经收集的广泛的临床和基因组数据和生物标本来确定基因修饰剂和蛋白质生物标志物，这些基因修饰剂和生物标志物可以预测这种毁灭性疾病的结果。我们的调查小组拥有进行这些实验所需的专业知识和记录。我们期望这项工作将为BA的生物学发病机制提供新的知识，并加快研究新的治疗方法的步伐。

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.