BCM/TCH CHOLESTATIC LIVER DISEASE CONSORTIUM

项目摘要 胆汁淤积性肝病，包括Alagille综合征、α-1抗胰蛋白酶缺乏症、胆汁酸合成 缺陷、胆道闭锁、囊性纤维化、线粒体肝病、进行性家族性肝内胆汁淤积 和原发性硬化性胆管炎，导致儿童期显著的发病率和死亡率， 需要进行肝移植没有一个单一的北美临床中心看到足够多的 这些疾病的患者，允许一个严格的方法来解决未解决的问题，包括 病因和发病机制，最佳诊断和治疗方法，以及影响疾病的因素 严重程度和预后。贝勒医学院和得克萨斯州的这一竞争性更新提案 儿童医院（CHN/TCH）寻求继续进行儿童肝病的研究活动 研究网络（ChiLDReN）。这一更新资金的申请包括一个坚定的承诺， 继续正在进行的研究工作和两个新的建议，一个新的试点和可行性临床试验应用 胆道闭锁和翻译协议集中在硬化性胆管炎的发病机制。临床 中心包括一组杰出的临床研究人员，他们在以下方面有着广泛的跟踪记录： 与儿科肝病相关的协同转化和临床研究迄今为止的业绩 正在进行的儿童营养素研究是一个典范，充分利用了占主导地位的市场 休斯顿大都市区（美国第五大）人口基数的份额和大 将TCH作为儿科肝病学和肝移植的四级中心的转诊模式。一名飞行员和 静脉注射NAC的可行性试验将作为一项开放标签研究，在接受 肝门肠吻合术治疗胆道闭锁（IND 135796和NCT 03499249）。主要结果指标将 重点关注胆汁流动的生物标志物。这项试验性研究中有希望的发现可以扩大到更大的规模 多中心研究作为ChiLDReN的一部分。所提出的翻译方案将使用宏基因组 全基因组测序评估硬化性胆管炎儿童的细菌粪便微生物组， 将微生物特征和细菌基因表达模式与表征为 新开发的儿童原发性硬化性胆管炎前瞻性观察研究。

Project Summary Cholestatic liver diseases including Alagille syndrome, alpha-1 antitrypsin deficiency, bile acid synthesis defects, biliary atresia, cystic fibrosis, mitochondrial hepatopathies, progressive familial intrahepatic cholestasis and primary sclerosing cholangitis, lead to significant morbidity and mortality in childhood, frequently necessitating liver transplantation. No single North American clinical center sees a large enough number of patients with these disorders to permit a rigorous approach to addressing unresolved questions including etiology and pathogenesis, optimal methods of diagnosis and treatment, and factors that influence disease severity and prognosis. This competitive renewal proposal from the Baylor College of Medicine and Texas Children's Hospital (BCM/TCH) seeks to continue ongoing research activities in the Childhood Liver Disease Research Network (ChiLDReN). This application for renewal funding includes a strong commitment to continuing the on-going research efforts and two new proposals, a novel pilot and feasibility clinical trial applied to biliary atresia and a translational protocol focused on the pathogenesis of sclerosing cholangitis. The clinical center at BCM/TCH includes an outstanding group of clinician investigators with an extensive track record in synergistic translational and clinical research relevant to pediatric liver diseases. Performance to date in the on-going studies of ChiLDReN has been exemplary and has taken full advantage of a predominant market share of the population base of the Houston metropolitan region (5th largest in the United States) and the large referral patterns to TCH as a quaternary center for Pediatric Hepatology and Liver Transplantation. A pilot and feasibility trial of intravenous NAC will be conducted as an open label investigation in infants undergoing hepatoportoenterstomy for biliary atresia (IND 135796 and NCT03499249). The primary outcome measure will focus on biomarkers of bile flow. Promising findings in this pilot study could be expanded to a larger scale multi-center investigation as part of ChiLDReN. The proposed translational protocol will use metagenomic whole genome sequencing to assess the bacterial fecal microbiome in children with sclerosing cholangitis and correlate microbial signatures and bacterial gene expression patterns with clinical phenotypes characterized in the newly developed prospective observational study of primary sclerosing cholangitis in children.