BCM/TCH CHOLESTATIC LIVER DISEASE CONSORTIUM

BCM/TCH 胆汁淤积性肝病联盟

• 批准号: 10019528
• 负责人: BENJAMIN L SHNEIDER
• 金额: $ 36.1万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-10 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10019528
• 关键词: Acetylcysteine; Address; Adjuvant Therapy; Alagille Syndrome; American; Bacterial Genes; Bile Acid Biosynthesis Pathway; Bile Acids; Bile fluid; Biliary Atresia; Biological Markers; Child; Child Health; Childhood; Clinical; Clinical Data; Clinical Research; Clinical Trials; Cystic Fibrosis; Defect; Development; Diagnosis; Disease; Duct (organ) structure; Enrollment; Etiology; Evidence based treatment; Feces; Fibrosis; Funding; Gene Expression Profile; Genomics; Hepatology; Hour; Impairment; Individual; Infant; Inflammatory Bowel Diseases; Intervention; Intravenous; Investigation; Lead; Leadership; Life; Liver; Liver diseases; Longitudinal Studies; Medicine; Metagenomics; Methods; Mitochondria; Morbidity - disease rate; Observational Study; Outcome; Outcome Measure; Pathogenesis; Patients; Pattern; Pediatric Hospitals; Performance; Phase; Pilot Projects; Progressive intrahepatic cholestasis; Protocols documentation; Research; Research Activity; Research Personnel; Role; Safety; Sampling; Sclerosing Cholangitis; Serum; Severity of illness; Testing; Texas; Translational Research; Treatment Factor; United States; Validation; Whole-Genome Shotgun Sequencing; alpha 1-Antitrypsin Deficiency; base; cholestatic liver disease; clinical center; clinical investigation; clinical phenotype; college; data warehouse; disease phenotype; feasibility trial; fecal microbiome; follow-up; genome sequencing; gut microbiome; improved; improved outcome; liver transplantation; longitudinal analysis; metropolitan; microbial; microbiome analysis; microbiome research; mortality; novel; open label; outcome forecast; pilot trial; population based; primary outcome; primary sclerosing cholangitis; prospective; research study; secondary outcome; stool sample; trial design; whole genome

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.

项目概要 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 和原发性硬化性胆管炎，经常导致儿童显着的发病率和死亡率 需要进行肝移植。没有一个北美临床中心能够看到足够多的患者 患有这些疾病的患者可以采取严格的方法来解决未解决的问题，包括 病因病机、最佳诊疗方法及影响疾病的因素 严重程度和预后。来自贝勒医学院和德克萨斯州的竞争性续签提案 儿童医院 (BCM/TCH) 寻求继续开展儿童肝脏疾病方面的持续研究活动 研究网络（ChiLDReN）。本次更新资金申请包括对以下方面的坚定承诺： 继续正在进行的研究工作和两项新提案、一项新颖的试点和可行性临床试验 胆道闭锁和专注于硬化性胆管炎发病机制的转化方案。临床上 BCM/TCH 中心包括一群杰出的临床研究人员，他们在以下方面拥有广泛的记录： 与儿科肝脏疾病相关的协同转化和临床研究。迄今为止的表现 正在进行的儿童研究堪称典范，并充分利用了主导市场 休斯敦都会区（美国第五大都会区）的人口基数比例 TCH 作为儿科肝病学和肝移植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开放标签调查在婴儿中进行 肝门肠造口术治疗胆道闭锁（IND 135796 和 NCT03499249）。主要结果指标将 关注胆汁流量的生物标志物。这项试点研究的有希望的结果可以扩大到更大范围 作为ChiLDReN 的一部分进行多中心调查。拟议的翻译协议将使用宏基因组 全基因组测序以评估患有硬化性胆管炎的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临床表型相关联 新开展的儿童原发性硬化性胆管炎前瞻性观察研究。