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 (TCH/BCM) 肝脏中心一直是 BARC 和 CLiC 的积极参与者，并且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 ChiLDREN 资助的临床、研究和教育目标。目标 1：临床中心继续参与 ChiLDREN 的各个方面。该中心自 2005 年以来参与了所有 BARC 和 CLiC 项目以及 CF 肝病联盟。我们的目标是继续参与，这为 BARC（POO3、P004、POO5）和 CLiC 的注册人数提供了高水平。临床基础设施得到广泛支持，人员经验丰富，再加上集中护理和研究，使该中心能够实现高水平的入组和纵向随访。我们还将参与 ChiLDREN 各方面的观察性和干预性试验。目标 2：探索适应小儿肝病的遗传决定因素。决定婴儿和儿童肝病结果的独特因素之一是个体基因构成的影响，最好的例子是这些儿童是否能很好地适应的短暂时间。我们假设，通过对个体患者基因组决定因素进行详细、广泛、公正的探索（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配为能够良好适应的儿童，并且那些不这样做的人。此外，我们希望这些信息能够实现有针对性的治疗发现。目标 3：设计并启动 1 期和 2 期临床试验，探索 Nor-UDCA 作为多种儿童胆汁淤积性和纤维化肝病的治疗剂。去甲熊去氧胆酸 (Nor-UDCA) 是 UDCA 的侧链修饰物，目前正在欧洲进行治疗成人胆汁淤积性肝病的 1 期试验。 Nor-UDCA 可能通过胆肝分流增强胆汁流量。我们假设 Nor-UDCA 将是一种安全有效的治疗药物，用于治疗特定的胆汁淤积性肝病儿童；特别是患有 ABCB4 疾病的患者，以及有胆汁纤维化/肝硬化或门静脉高压证据的 BA 和 CFLD 儿童。由于目前尚无针对胆汁淤积的有效药物疗法，因此对这种研究药物的安全性和有效性的适当探索完全适合 ChiLDREN 的职责，并且可以说，它是唯一可以测试此类潜在疗法的联盟。