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: 9135724
• 负责人: BENJAMIN L SHNEIDER
• 金额: $ 11.31万
• 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/9135724
• 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; Cystic Fibrosis; Data; Data Analyses; Data Collection; Development; Diagnosis; Disease; Education; Enrollment; Epigenetic Process; Fibrosis; Genetic; Health; 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; Outcome; Outcome Measure; Participant; Pathogenesis; Pathology; Patients; Pentoxifylline; Phase II Clinical Trials; 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; Staging; Stem cells; Testing; Therapeutic; Therapeutic Agents; Tissues; Transplantation; Ultrasonography; United States; United States National Institutes of Health; base; design; elastography; experience; follow-up; imaging biomarker; improved; liver injury; liver transplantation; methylxanthine; minimal risk; neonatal hepatitis; neonatal sepsis; novel; phase II trial; pre-clinical research; primary outcome; programs; repository; sample collection; secondary outcome; targeted treatment

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 (ChiLDREN) 为改善患有严重肝病的儿童的生活提供了前所未有的机会。该临床中心持续做出富有成效的贡献 ChiLDREN 的提出有 3 个主要目标： I. 联盟贡献：建立了一个组织良好的基础设施，能够实现高水平的患者登记、数据和标本收集，并融入美国最大的儿科肝病项目之一，拥有丰富的经验研究人员和协调员，以及临床研究方面的出色记录。此外，我们建议对临床数据和胆道闭锁肝组织进行分析，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，更好地预测和确定肝门肠造口术后的结果。二.辅助研究：几项独特的研究与该提案相关，这些研究源自该临床中心的卓越优势和初步研究：(i) 将进一步评估血清纤维化和新型成像标志物，以改善儿童疾病的诊断和监测肝纤维化； (ii) 在平行机制研究中，我们正在进一步探索胆道闭锁和CFLD发病机制的分子机制，研究肝组织和血清中的表观遗传、遗传和基本纤维发生机制，并建议将这些研究扩展到储存组织和数据分析。三．临床试验：为了评估新的抗纤维形成疗法，正在对新诊断的 BA 婴儿进行一项二期临床试验，对己酮菲林 (PTX) 进行 II 期临床试验，PTX 是一种已知的抗纤维形成抗炎剂，已证明对婴儿安全。确定 PTX 是否对 BA 具有足够的生物活性，且风险最小，值得进一步研究。我们假设 PTX 将是一种安全有效的治疗药物，可改善患有进行性胆汁纤维化/肝硬化的特定儿童的预后。由于目前还没有有效的 对于儿童疾病的医学疗法，对这种药物的安全性和有效性的适当探索完全符合 ChiLDREN 的职责，ChiLDREN 具有独特的能力来大规模研究这种新疗法。我们希望继续为实现 ChiLDREN 的所有目标做出富有成效的贡献，帮助改变患有肝病的儿童。我们期望提供高价值的参与，利用完善的 ChiLDREN 血清和组织存储库来寻找非侵入性生物标志物和更好的结果预测，对这些疾病的分子发病机制开展富有成效的机制研究，并帮助领导研究新颖的安全疗法，以帮助填补当前的治疗空白。