Clinical Center: ChiLDReN (Childhood Liver Disease Research Network)

描述(由申请人提供)：肝脏疾病是导致婴儿和儿童发病率和死亡率的主要原因。构成“儿科肝病”的疾病是个别罕见的，这阻碍了对其病因/病理生理学的研究。由于对这一基本认识的缺陷，大多数患者缺乏有效的治疗策略。这反过来又导致许多儿童进展到终末期肝病，需要进行原位肝移植。儿科肝脏移植约占所有肝移植手术的10%，其中大多数的适应症存在于儿童肝病研究网络(CHILDA)将要研究的疾病中。这个网络结合了几家个别成功的大型临床研究企业的努力，招募受试者并进行严格的临床研究和试验，以期建立具有良好特征的患者队列，这些患者可以在其疾病过程的自然历史中进行跟踪，并可用于新兴疗法的试验。此外，与临床数据相联系的生物标本为病因学(遗传和其他)研究以及基因表达和表观基因组学对疾病表达和进展的影响以及对治疗的反应提供了燃料。我们建议作为一个中心参与儿童问题，在这个中心，调查人员在整个联合体内的几个关键调查领域拥有丰富的专业知识。自成立以来，我们的中心一直是儿童(及其前身联盟)进行的每项研究的主要捐赠者之一。我们期望继续为儿童的表现作出重大贡献，以实现其成功消除儿科肝病这一导致婴幼儿发病率和死亡率的主要原因的目标。我们中心的具体目标包括：a)作为领先的儿童临床中心全面参与；以及b)利用目前从儿童生物信息库获得的标本，开发一种新的纤维化生物标志物，并确定发育信号通路Hedgehog的激活是否有助于胆道闭锁纤维化的发展。

DESCRIPTION (provided by applicant): Liver disease is a major cause of infant and childhood morbidity and mortality. The diseases comprising "pediatric liver diseases" are individually rare, which has hindered the study of their causes/pathophysiologies. As a result of this basic defect in understanding effective therapeutic strategies are lacking for most of them. This in turn results in many children with progressing to end-stage liver disease necessitating orthotopic liver transplantation. Pediatric liver transplants comprise approximately 10% of all liver transplants performed, and the indications for most of them lie among the diseases to be studied in the Childhood Liver Disease Research Network (ChiLDReN). This network combines the efforts of several large and individually successful clinical research enterprises to recruit subjects and carry them through rigorous clinical studies and trials with the expectation of establishing well-characterized patient cohorts that can be followed through the natural history of their disease process and which can be accessed for trials of emerging therapies. In addition, the biological specimens linked to clinical data provide the fuel for studies of etiology (genetic and other) and the influences of gene expression and epigenomics on disease expression and progression, as well as response to therapy. We propose to participate in ChiLDReN as a center wherein investigators have substantial expertise in several of the key areas of investigation within the consortium as a whole. Our center has been one of the top contributors of subjects to every study undertaken by ChiLDReN (and its predecessor consortia) over the term of its existence. We expect to continue to contribute substantially to the performance of ChiLDReN in achieving its goal of successfully eliminating pediatric liver disease as a major cause of infant and childhood morbidity and mortality. The specific aims at our center include: a) to participate fully as a leading clinical center in ChiLDReN; and b) to utilize the currently available specimens from the ChiLDReN biorepository to develop a novel biomarker for fibrosis and determine if activation of the developmental signaling pathway hedgehog contributes to the development of fibrosis in biliary atresia.