Clinical Center for ChiLDREN: Pathogenesis, Biomarkers, and Antifibrotic Therapy

ChiLDREN 临床中心：发病机制、生物标志物和抗纤维化治疗

• 批准号: 9317473
• 负责人: BENJAMIN L SHNEIDER
• 金额: $ 32.88万
• 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 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9317473
• 关键词: 1 year old; Acute; Adult; Ancillary Study; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Biliary; Biliary Atresia; Bilirubin; Biological; Biological Markers; Biological Models; Biopsy; Caffeine; Charge; Child; Child Care; Childhood; Cholestasis; Cirrhosis; Clinical; Clinical Data; Clinical Research; Clinical Research Protocols; Clinical Trials; Collection; Data; Data Analyses; Data Collection; Development; Diagnosis; Disease; Education; Enrollment; Epigenetic Process; Fibrosis; Genetic; Hepatic Fibrogenesis; Hepatology; Image; Infant; Investigation; Lead; Link; Liver; Liver Cirrhosis; Liver Fibrosis; Liver Regeneration; Liver diseases; Medical; Mission; Molecular; Monitor; Neural Network Simulation; Newly Diagnosed; Nuclear Receptors; Nutritional status; Oral; Outcome; Outcome Measure; Participant; Pathogenesis; Pathology; Patients; Pentoxifylline; Phase II Clinical Trials; Phenotype; Portal Hypertension; Prevention; Property; Protocols documentation; Public Health; Publications; Radiology Specialty; Recording of previous events; Research; Research Design; Research Infrastructure; Research Personnel; Resources; Safety; Serum; Signal Transduction; Site; Specimen; Stem cells; Testing; Therapeutic; Therapeutic Agents; Tissues; Transplantation; Treatment Efficacy; Ultrasonography; United States; United States National Institutes of Health; base; design; elastography; experience; follow-up; imaging biomarker; improved; improved outcome; liver cystic fibrosis; liver injury; liver transplantation; methylxanthine; minimal risk; neonatal hepatitis; neonatal sepsis; new therapeutic target; novel; novel marker; novel therapeutics; outcome prediction; phase II trial; primary outcome; programs; public health relevance; repository; sample collection; secondary outcome

DESCRIPTION (provided by applicant): The Childhood Liver Disease Research and Education Network (ChiLDREN) provides an unprecedented opportunity to improve the lives of children with serious liver diseases. Continued productive contributions of this Clinical Center to ChiLDREN are proposed with 3 major aims: I. Consortium Contribution: A well-organized infrastructure that enables a high level of patient enrollment and data and specimen collection is well established, integrated into one of the largest pediatric hepatology programs in the United States with experienced investigators and coordinators, and an excellent track record in clinical research. In addition, we propose leading an analysis of clinical data and biliary atresia liver tissue to better evaluate phenotypic and clinicopathological correlations and, by competing outcomes, multivariate and neural network modeling, to better predict and determine outcomes after hepatoportenterostomy. II. Ancillary Studies: Several unique studies are linked to this proposal, developing from this Clinical Center's pre-eminent strengths and preliminary studies: (i) serum fibrosis and novel imaging markers will be further evaluated to improve diagnosis and monitor liver fibrosis in ChiLDREN diseases; (ii) in parallel mechanistic studies, we are further exploring the molecular mechanisms of pathogenesis of biliary atresia and CFLD, studying epigenetic, genetic, and fundamental fibrogenetic mechanisms in liver tissue and serum, and we propose extending these studies to repository tissue and data analysis. III. Clinical Trial: To evaluate new antifibrogenic therapies, a Phase II clinical trial of pentoxyfilline (PTX), a known antifibrogenic antiinflammatory agent of proven safety in infants, is being conducted in infants with newly-diagnosed BA (registered with clinical trials.gov) to determine whether PTX has sufficient biological activity against BA, with minimal risk, which warrants further study. We hypothesize that PTX will be a safe and effective therapeutic agent to improve outcomes for select children with progressive biliary fibrosis/cirrhosis. Since there are currently no effective medical therapies for CHiLDREN diseases, proper exploration of the safety and efficacy of this agent would perfectly fit within the charge of ChiLDREN, which is uniquely poised to examine such novel therapies on a large scale. We hope to renew our productive contribution to achieving all the aims of ChiLDREN, helping to make a difference for children with liver diseases. We expect to provide high-value participation, capitalize on the well- developed ChiLDREN serum and tissue repository in the search for non-invasive biomarkers and better prediction of outcomes, embark upon fruitful mechanistic studies on the molecular pathogenesis of these diseases, and help lead investigations of novel safe therapies to help fill the current therapeutic void.

描述（由申请人提供）：儿童肝病研究和教育网络（儿童）为改善严重肝病儿童的生活提供了前所未有的机会。这个临床中心的持续生产贡献 提出了3个主要目的的儿童：I。财团的贡献：一个组织良好的基础设施，使高水平的患者入学率和数据和标本收集良好，并融入了美国经验丰富的研究人员和协调员，以及在临床研究中具有出色的往绩。此外，我们提出了对临床数据和胆道闭锁组织的分析，以更好地评估表型和临床病理学相关性，并通过竞争结果，多变量和神经网络建模，以更好地预测和确定肝脊髓结构术后的结局。 ii。辅助研究：基于该临床中心的杰出优势和初步研究发展的几项独特研究与该建议有关：（i）将进一步评估血清纤维化和新型成像标记，以改善儿童疾病中诊断和监测诊断和监测肝纤维化； （ii）在平行的机理研究中，我们正在进一步探索胆道闭锁和CFLD发病机理的分子机制，研究肝组织和血清中的表观遗传学，遗传和基本纤维遗传学机制，我们建议将这些研究扩展到重建组织和数据分析。 iii。临床试验：为了评估新的抗基因疗法，在婴儿新诊断的BA的婴儿中，正在对婴儿进行了五氧化易蛋白（PTX）的II期临床试验（PTX），该试验是一种已知的抗纤维化抗炎抗炎剂，该试验是在新诊断的BA的婴儿中进行的（通过临床试验进行了注册），以确定PTX是否有足够的carrations对BAIL ACTION BAIL ACTION BAIM ATCOLITS ACTION BAIM ACTICTIAD BAIMIMINE，该活动是对BA的一部分。我们假设PTX将是一种安全有效的治疗剂，可以改善患有进行性胆道纤维化/肝硬化的儿童的预后。由于目前没有效果 儿童疾病的医疗疗法，对该药物的安全性和有效性的适当探索将完全适合儿童，这是一个独特的准备，可以大规模检查这种新型疗法。我们希望为实现儿童的所有目标做出生产贡献，从而为肝病儿童带来改变。我们期望提供高价值的参与，利用良好的儿童血清和组织仓库，以寻求非侵入性生物标志物，并更好地预测结果的预测，并开始对这些疾病的分子发病机理进行成果的机械研究，并帮助新型安全疗法进行领导研究，以帮助填充当前的治疗效果。