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

描述(申请人提供)：儿童肝病研究和教育网络(CHILDS)为改善严重肝病儿童的生活提供了前所未有的机会。该临床中心对以下方面的持续有效贡献 儿童的建议有三个主要目标：i.联合体贡献：一个组织良好的基础设施，使高水平的患者登记和数据和样本收集得到很好的建立，并与美国最大的儿科肝病项目之一相结合，拥有经验丰富的研究人员和协调员，以及良好的临床研究记录。此外，我们建议领导对临床数据和胆道闭锁肝组织的分析，以更好地评估表型和临床病理相关性，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静脉吻合术后的结果。辅助研究：有几项独特的研究与这一提议有关，这些研究是基于本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记物，以改进儿童疾病的诊断和监测肝纤维化；(Ii)在平行的机制研究中，我们正在进一步探索胆道闭锁和CFLD发病的分子机制，研究肝组织和血清中的表观遗传学、遗传学和基本的纤维形成机制，我们建议将这些研究扩展到存储库组织和数据分析。III.临床试验：为了评估新的抗纤维化疗法，已知的抗纤维化抗炎药戊氧非汀(PTX)正在婴儿中进行第二阶段临床试验(已在临床试验网站注册)，以确定PTX是否在风险最小的情况下对BA具有足够的生物活性，值得进一步研究。我们推测，PTX将是一种安全有效的治疗药物，可以改善部分进行性胆汁性纤维化/肝硬变患儿的预后。由于目前还没有有效的 对于儿童疾病的医疗疗法，对这种制剂的安全性和有效性的适当探索将完全符合儿童的责任，儿童正准备大规模地研究这种新的疗法。我们希望再次为实现儿童的所有目标做出富有成效的贡献，帮助为患有肝病的儿童做出改变。我们期望提供高价值的参与，利用发展良好的儿童血清和组织储存库来寻找非侵入性生物标记物和更好地预测结果，开始对这些疾病的分子发病机制进行富有成效的机制研究，并帮助领导对新的安全疗法的研究，以帮助填补目前的治疗空白。

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.