Advancing our Understanding of Rare Pediatric Liver Diseases

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）的延续申请。在过去的十年里，通过协调努力，八个胆汁淤积性儿科疾病的调查已经取得了进展，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。关于ChiLDReN研究的罕见儿科肝病的发病机制、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护理的质量和效率。在过去的10年里，CHOP一直是ChiLDReN的高产成员。在本申请中，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，我们还列入了一项关于我们可以向该网络提供的遗传学和病理学服务的建议。胆道闭锁（BA）是一种进行性特发性肝外胆道系统坏死性炎症性疾病，在婴儿期出现，占美国所有儿科肝移植的50%。目前，在诊断时，没有准确的方法来预测BA儿童的结局。一个可靠的预测临床结果的算法将是有价值的，在临床试验中定义预后和分层患者。此外，对潜在分子机制的进一步理解将促进新疗法的开发。在我们的科学建议中，我们将测试基因组和蛋白质组学因素可以预测BA结果的假设。利用我们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，以确定改变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2岁以上的胆道闭锁儿童中检测到的变异，这些儿童与未存活的儿童相比。我们还建议进行深入研究，以调查GWAS中确定的变体的功能后果。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临床结局的血清蛋白。我们的研究将利用ChiLDREN联盟已经收集的广泛的临床和基因组数据以及生物标本，以确定可以预测这种毁灭性疾病结果的遗传修饰剂和蛋白质生物标志物。我们的调查团队拥有进行这些实验所需的专业知识和记录。我们预计，这项工作将有助于对BA的生物学发病机制的新知识，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.