The Childhood Liver Disease Research and Education Network (ChilDREN)

德克萨斯儿童医院/贝勒医学院肝脏中心(TCH/BCM)一直是BARC和CLIC的积极参与者，并对有机会继续参与感到兴奋。该中心的首要目标是帮助推进儿童补助金的临床、研究和教育目标。目标1：继续参与临床中心对儿童各个方面的参与。自2005年以来，该中心参与了所有BARC和CLIC项目，以及CF肝病联合会。我们的目标是继续参与，这为BARC(PO3，P004，POO5)和CLIC提供了高水平的注册。临床基础设施得到了广泛的支持，经验丰富的人员，再加上集中的护理和研究，使该中心能够进行高水平的登记和纵向跟踪。我们还将在儿童中进行所有方面的观察性和干预性试验。目的2：探讨儿童肝病适应的遗传决定因素。在决定婴儿和儿童肝脏疾病结局的独特方面中，个人基因构成的贡献是最好的例证，最好的例证是这些儿童是否能很好地适应的短时间线。我们假设，通过对个体患者基因组决定因素的详细、广泛、不偏不倚的探索(例如，整个外显子组测序或对核受体途径的重点研究)，我们将能够将儿童的遗传分类归类为能够很好适应的人和不能适应的人。此外，我们预计这些信息将允许有针对性的治疗发现。目的3：设计并启动1期和2期临床试验，探索Nor-UDCA作为一种治疗儿童胆汁淤积性和纤维性肝病的药物。Nor-熊去氧胆酸(Nor-UDCA)是UDCA的一种侧链修饰物，目前正在欧洲进行成年人胆汁淤积性肝病的第一阶段试验。NOR-UDCA可能通过胆肝分流增加胆汁流量。我们推测，NOR-UDCA将是一种安全有效的治疗药物，适用于有胆汁淤积性肝病的儿童，特别是那些患有ABCB4病的儿童，以及有胆道纤维化/肝硬变或门脉高压症状的BA和CFLD儿童。由于目前还没有有效的治疗胆汁淤积的药物，对这种研究药物的安全性和有效性进行适当的探索将完全符合儿童的需求，而且可以说，它是唯一可以测试这种潜在疗法的联盟。

The Liver Center at Texas Children's Hospital/Baylor College of Medicine (TCH/BCM) has been an active participant in BARC and CLiC, and is excited by the opportunity to continue participation. The overarching aims of this Center are to help advance the clinical, research, and educational goals of the ChiLDREN grant. Aim 1: Continued Clinical Center participation in all aspects of ChiLDREN. This Center has participated in all BARC & CLiC programs since 2005, as well as the CF Liver Disease Consortium. We Aim to continue our participation, which has provided high levels of enrollment into BARC (POO3, P004, POO5) and CLiC. The clinical infrastructure is broadly supportive, and the personnel experienced, which, along with centralized care and research, allows this Center a high level of enrollment and longitudinal follow-up. We will also engage in all aspects of observational and interventional trials in ChiLDREN. Aim 2: Explore the genetic determinants of adaptation to pediatric liver disease. Among the unique aspects that determine outcomes of liver disease in infants and children, is the contribution of the individual's genetic makeup, best exemplified by the short timelines that underlie whether these children will adapt well or not. We hypothesize that by detailed, broad-based, unbiased exploration of individual patient genomic determinants (e.g., whole exome sequencing or focused studies of nuclear receptor pathways), we will be able to assign genetic categorization of children into those able to adapt well, and those who do not. Moreover, we expect this information to allow for targeted therapeutic discoveries. Aim 3: Design and initiate Phase 1 and 2 clinical trials exploring Nor-UDCA as a therapeutic agent in a variety of cholestatic and fibrosing liver diseases in children. Nor-ursodeoxycholic acid (Nor-UDCA), a side chain modification of UDCA, is currently undergoing Phase 1 trials in Europe for cholestatic liver diseases in adults. Nor-UDCA enhances bile flow, perhaps through cholehepatic shunting. We hypothesize that Nor- UDCA will be a safe and effective therapeutic agent for select children with cholestatic liver disease; specifically those with ABCB4 disease, as well as children with BA & CFLD who have evidence of biliary fibrosis/cirrhosis or portal hypertension. Since there are currently no effective medical therapies for cholestasis, proper exploration of the safety and efficacy of this investigational agent would perfectly fit within the charge of ChiLDREN, and, arguably, is the only Consortium that could test such potential therapeutics.