The Childhood Liver Disease Research and Education Network (ChilDREN)

儿童肝病研究和教育网络 (ChilDREN)

• 批准号: 8011891
• 负责人: SAUL J. KARPEN
• 金额: $ 15万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-10 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8011891
• 关键词: Achievement; Adult; Animal Model; Animals; Basic Science; Bile Acids; Bile fluid; Biliary; Caring; Charge; Child; Childhood; Cholestasis; Cirrhosis; Clinical; Clinical Research; Clinical Trials; Disease; Education; Enrollment; Europe; Fibrosis; Genetic; Genetic Determinism; Genomics; Goals; Grant; Hepatocyte; Hepatology; Human Genome; Human Resources; Individual; Infant; Investigation; Life; Liver; Liver diseases; Medical; Medicine; Modification; Nuclear Receptors; Operative Surgical Procedures; Outcome; Participant; Pathology; Pathway interactions; Patients; Pediatric Hospitals; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Portal Hypertension; Regulator Genes; Research; Resources; Safety; Side; Testing; Texas; Therapeutic; Therapeutic Agents; TimeLine; Ursodeoxycholic Acid; Work; base; clinical infrastructure; college; design; exome; experience; follow-up; genome sequencing; novel; programs; therapeutic target; transplantation medicine

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.

德克萨斯州儿童医院/贝勒医学院（TCH/BCM）的肝脏中心一直积极参与BARC和CLIC，并为继续参与的机会感到兴奋。该中心的总体目的是帮助促进儿童赠款的临床，研究和教育目标。目标1：持续临床中心参与儿童的各个方面。自2005年以来，该中心已参加了所有BARC＆CLIC计划，以及CF肝病联盟。我们的目标是继续参与，这为BARC（Poo3，P004，Poo5）和Clic提供了高水平的入学率。临床基础设施具有广泛的支持，并且经历的人员与集中的护理和研究一起提供了该中心的高水平入学率和纵向随访。我们还将参与儿童观察和介入试验的各个方面。目标2：探索适应小儿肝病的遗传决定因素。在确定婴儿和儿童肝病结局的独特方面之一是个人的遗传构成的贡献，最好用这些儿童适应是否适应的时间表的简短时间表来体现。我们假设，通过对个体患者基因组决定因素（例如，整个外显子组测序或对核受体途径的研究）进行详细的，无偏见的探索，我们将能够将儿童的遗传分类分配到能够适应良好的人和不能适应的孩子中。此外，我们希望这些信息允许有针对性的治疗发现。 AIM 3：设计和启动第1阶段和第2阶段的临床试验，探索诺卡（Nor-udca）作为儿童多种胆汁淤积和纤维化肝脏疾病的治疗剂。 UDCA的侧链修饰Nor-甲氧氧化胆酸（Nor-udca）目前正在欧洲进行成人胆汁淤积性肝病的1期试验。诺卡（Nor-udca）可能通过cholehepatic分流来增强胆汁的流动。我们假设Nor- UDCA将是胆汁淤积性肝病儿童的安全有效的治疗剂。特别是患有ABCB4疾病的患者以及具有胆道纤维化/肝硬化或门静脉高压迹象的BA＆CFLD儿童。由于目前尚无有效的胆汁淤积医疗疗法，因此对该研究剂的安全性和功效的适当探索将完全适合儿童的负责人，并且可以说，是唯一可以测试这种潜在治疗剂的财团。