Clinical Center for Cholestatic Liver Disease in Children

儿童胆汁淤积性肝病临床中心

• 批准号: 10631943
• 负责人: Alexander Miethke
• 金额: $ 80.1万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10631943
• 关键词: Acetylcysteine; Acute; Alagille Syndrome; Ancillary Study; Antioxidants; Bile Acids; Biliary; Biliary Atresia; Biological Markers; Caring; Child; Child Care; Childhood; Cholestasis; Clinical; Clinical Data; Clinical Research; Clinical Research Protocols; Clinical Trials; Collection; Cystic Fibrosis; Data; Data Analyses; Data Coordinating Center; Defect; Development; Disease; Disease Outcome; Drainage procedure; Education; Enrollment; Epithelium; Etiology; Funding; Genetic; Goals; Grant; IL8 gene; Infant; Infrastructure; Injury; Institutional Review Boards; Intervention; Intestines; Intravenous Immunoglobulins; Knowledge; Leadership; Liver; Liver Fibrosis; Liver diseases; Logic; Longitudinal Studies; Magnetic Resonance Imaging; Maintenance; Matrilysin; Measures; Mitochondria; Molecular; National Institute of Diabetes and Digestive and Kidney Diseases; Neonatal; Observational Study; Outcome; Paper; Pathogenesis; Pathology; Patients; Performance; Portal Hypertension; Positioning Attribute; Progressive intrahepatic cholestasis; Prospective Studies; Protocols documentation; Pruritus; Publications; Quality of life; RNA purification; Radiology Specialty; Reporting; Research; Research Infrastructure; Research Personnel; Role; Safety; Serum; Services; Sodium; Steroids; Tissue Sample; Tissues; Translational Research; U-Series Cooperative Agreements; United States National Institutes of Health; Vancomycin; Work; alpha 1-Antitrypsin Deficiency; bile acid transporter; chronic liver disease; clinical center; clinical development; clinical research site; clinical translation; clinical trial protocol; data submission; design; disease natural history; efficacy evaluation; elastography; improved; improved outcome; innovation; intrahepatic; liver cystic fibrosis; liver stiffness; member; open label; primary sclerosing cholangitis; prospective; protocol development; response; small molecule inhibitor; support network; symposium; translational study

PROJECT SUMMARY/ABSTRACT We propose to remain a Member of the Childhood Liver Disease Research Network (ChiLDReN). As a Charter Member of the Network, our proposal represents a logical extension of the long-standing commitment of our Center to improve the care of children with chronic liver disease through innovative patient-based research. In the previous member of the Network, we worked collaboratively with investigators from other Centers and with the Data Coordinating Center to build a strong infrastructure to conduct patient-based studies on biliary atresia, cholestatic syndromes, mitochondrial hepatopathies and cystic fibrosis, with initial work to develop an observational and interventional protocol for children with primary sclerosing cholangitis (PSC). Our key contributions in the previous cycle included: 1) leadership and/or partnership in the development of network-wide clinical studies, with data analyses and publication of 11 original papers; 2) completion of the first two clinical trials (the steroid trial START and the IV-IG trial PRIME); 3) high enrollment and retention of subjects into prospective studies, including the new FORCE study; 4) timely processing of liver tissue by the staff of RNA Purification Service, Bile Acid Analysis Service, and Pathology Service to support Network studies; and 5) co-leading the organization of an NIH symposium on biliary atresia, with publication of its proceedings. We look forward to significantly contributing to the scientific goals and operational excellence of ChiLDReN through three aims. In Aim 1, we will enroll subjects into prospective ChiLDReN protocols to enable observational studies and translational science. This will be done by pursuing high enrollment rate of subjects into approved protocols, with the timely collection and submission of data and tissue samples to meet the enrollment goals established by the Network. In Aim 2, we will develop and implement research protocols for clinical trials. We are working with Network investigators to conduct a trial to determine the efficacy and safety of a small molecule inhibitor of the intestinal sodium-dependent bile acid transporter (IMAGINE-II trial) in children with cholestasis-associated pruritus. We are also developing a clinical trial to determine the efficacy of Vancomycin in children with PSC. And in Aim 3, we propose a new clinical trial focusing on the use of anti- oxidants to decrease biliary injury in infants who acquire biliary drainage after hepatoportoenterostomy for biliary atresia. We also propose an ancillary study to determine the role of matrix metalloproteinase-7 as a biomarker of hepatic fibrosis in biliary atresia. By pursuing the three aims, we will be well positioned to fully execute the new Network aims of pursuing translational science projects and conducting trials to improve the outcome of children with cholestatic liver diseases.

项目摘要/摘要 我们建议仍然是儿童肝病研究网络（儿童）的成员。作为 网络的特许成员，我们的建议代表了长期承诺的逻辑扩展 通过创新的患者，我们中心改善慢性肝病儿童的护理 研究。在该网络的先前成员中，我们与其他的调查人员合作 中心和数据协调中心，以建立强大的基础设施来进行基于患者的研究 关于胆道闭锁，胆固醇综合征，线粒体肝病和囊性纤维化，最初的工作至 为原发性硬化性胆管炎（PSC）的儿童制定观察和介入方案。我们的 上一个周期中的主要贡献包括：1）开发领导和/或伙伴关系 网络范围内的临床研究，以及11个原始论文的数据分析和发表； 2）第一个完成 两项临床试验（类固醇试验开始和IV-IG试验Prime）； 3）高注册和保留 受试者进行前瞻性研究，包括新的力量研究； 4）及时处理肝组织 RNA净化服务的工作人员，胆汁酸分析服务和病理服务以支持网络 研究； 5）共同主持了NIH关于胆道闭锁的研讨会的组织 程序。我们期待着为科学目标和运营卓越的贡献 儿童通过三个目标。在AIM 1中，我们将注册受试者参加潜在的儿童协议，以实现 观察研究和转化科学。这将通过追求高级受试者的招生率来完成 及时收集和提交数据和组织样本以满足批准的协议 网络建立的入学目标。在AIM 2中，我们将为 临床试验。我们正在与网络调查人员合作进行试验以确定功效和安全性 肠道钠依赖性胆汁酸转运蛋白的小分子抑制剂（Imagion-II试验） 患有胆汁淤积相关的儿童。我们还正在开发一项临床试验，以确定 PSC儿童的万古霉素。在AIM 3中，我们提出了一项新的临床试验，重点是使用抗 氧化剂可减少肝索肠术后获得胆道排水的婴儿的胆道损伤 胆道闭锁。我们还提出了一项辅助研究，以确定基质金属蛋白酶7的作用 胆道闭锁的肝纤维化生物标志物。通过追求这三个目标，我们将有能力完全 执行新的网络目标，即追求转化科学项目并进行试验以改善 患有胆汁淤积性肝病的儿童的结果。

项目成果

Large-scale proteomics identifies MMP-7 as a sentinel of epithelial injury and of biliary atresia.

• DOI: 10.1126/scitranslmed.aan8462
• 发表时间: 2017-11-22
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Lertudomphonwanit C;Mourya R;Fei L;Zhang Y;Gutta S;Yang L;Bove KE;Shivakumar P;Bezerra JA
• 通讯作者: Bezerra JA

Exome Sequencing in Individuals with Isolated Biliary Atresia.

孤立性胆道闭锁个体的外显子组测序。

• DOI: 10.1038/s41598-020-59379-4
• 发表时间: 2020
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Rajagopalan,Ramakrishnan;Tsai,EllenA;Grochowski,ChristopherM;Kelly,SusanM;Loomes,KathleenM;Spinner,NancyB;Devoto,Marcella
• 通讯作者: Devoto,Marcella

Dendritic cells regulate natural killer cell activation and epithelial injury in experimental biliary atresia.

• DOI: 10.1126/scitranslmed.3002069
• 发表时间: 2011-09-28
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Saxena V;Shivakumar P;Sabla G;Mourya R;Chougnet C;Bezerra JA
• 通讯作者: Bezerra JA

Treatment of bile acid amidation defects with glycocholic acid.

• DOI: 10.1002/hep.27401
• 发表时间: 2015-01
• 期刊: HEPATOLOGY
• 影响因子: 13.5
• 作者: Heubi, James E.;Setchell, Kenneth D. R.;Jha, Pinky;Buckley, Donna;Zhang, Wujuan;Rosenthal, Philip;Potter, Carol;Horslen, Simon;Suskind, David
• 通讯作者: Suskind, David

Gene expression signature for biliary atresia and a role for interleukin-8 in pathogenesis of experimental disease.

• DOI: 10.1002/hep.27045
• 发表时间: 2014-07
• 期刊: HEPATOLOGY
• 影响因子: 13.5
• 作者: Bessho, Kazuhiko;Mourya, Reena;Shivakumar, Pranavkumar;Walters, Stephanie;Magee, John C.;Rao, Marepalli;Jegga, Anil G.;Bezerra, Jorge A.
• 通讯作者: Bezerra, Jorge A.