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.

德克萨斯儿童医院/贝勒医学院肝脏中心（TCH/BCM）一直是BARC和CLiC的积极参与者，并对有机会继续参与感到兴奋。该中心的首要目标是帮助推进儿童基金的临床、研究和教育目标。目标1：继续临床中心参与儿童的各个方面。自2005年以来，本中心参与了所有BARC和CLiC项目，以及CF肝脏疾病联盟。我们的目标是继续我们的参与，这为BARC （POO3, P004, POO5）和CLiC提供了高水平的入学率。临床基础设施广泛支持，人员经验丰富，加上集中的护理和研究，使该中心具有高水平的入组率和纵向随访。我们还将参与儿童观察性和干预性试验的各个方面。目的2：探讨儿童肝病适应的遗传决定因素。在决定婴儿和儿童肝病结果的独特方面中，个体基因构成的贡献是最好的例子，这些儿童是否能很好地适应的时间很短。我们假设，通过对个体患者基因组决定因素的详细、广泛、无偏见的探索（例如，全外显子组测序或核受体途径的重点研究），我们将能够将儿童的遗传分类分为能够很好地适应环境的儿童和不能很好地适应环境的儿童。此外，我们希望这一信息能够用于有针对性的治疗发现。目标3：设计并启动i期和ii期临床试验，探索no - udca作为各种儿童胆汁淤积症和纤维化性肝病的治疗药物。无熊去氧胆酸（no -ursodeoxycholic acid, no -UDCA）是UDCA的一种侧链修饰，目前正在欧洲进行治疗成人胆汁淤积性肝病的i期临床试验。无udca增强胆汁流动，可能通过肝胆分流。我们假设Nor- UDCA将是一种安全有效的治疗胆汁淤积性肝病的药物；特别是ABCB4疾病患者，以及有胆道纤维化/肝硬化或门脉高压证据的BA和CFLD儿童。由于目前还没有有效的药物治疗胆汁淤积症，因此对这种研究药物的安全性和有效性的适当探索将完全适合ChiLDREN的职责，并且可以说，它是唯一可以测试这种潜在治疗方法的联盟。