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、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症 和原发性硬化性胆管炎，在儿童时期经常导致显著的发病率和死亡率 有必要进行肝脏移植。没有一家北美临床中心能看到足够多的 这些疾病的患者允许采取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。这项由贝勒医学院和德克萨斯州提出的竞争性续签提案 儿童医院(BCM/TCH)寻求继续进行儿童肝病的研究活动 研究网络(儿童)。这份续签资金申请包括对 继续正在进行的研究工作和两项新建议，应用了一项新的中试和可行性临床试验 到胆道闭锁和一项专注于硬化性胆管炎发病机制的翻译方案。临床部 BCM/TCH中心包括一批杰出的临床医生研究人员，他们在 与儿科肝病相关的协同式翻译和临床研究。到目前为止的表现 正在进行的儿童研究堪称典范，并充分利用了一个占主导地位的市场 休斯敦大都市区的人口基数(美国第五大)和 TCH作为儿科肝病和肝移植第四中心的转诊模式。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治疗的婴儿中进行 胆道闭锁的肝门肠吻合术(IND 135796和NCT03499249)。主要结果衡量标准将是 关注胆汁流动的生物标志物。这项初步研究中有希望的发现可以扩大到更大的规模。 作为儿童的一部分，多中心调查。拟议的翻译协议将使用元基因组学 全基因组测序评估硬化性胆管炎和慢性胆管炎患儿的细菌粪便微生物群 微生物特征和细菌基因表达模式与临床表型的相关性 儿童原发性硬化性胆管炎最新前瞻性观察研究。

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.