Atlanta Center for the Childhood Liver Disease Research Network (ChiLDReN)

项目摘要 该中心的首要目标是帮助推进临床，研究和教育目标的 ChiLDReN赠款，特别强调从事尖端基因组研究作为基础， 发现、创新和改善结果和护理。因此，本申请的目的不是 只为所有符合ChiLDReN入学标准的儿童提供全面的研究机会 在整个美国东南部，但要开始1个试点临床试验和2个基因组为中心的 翻译目的：目的1：继续在ChiLDReN的各个方面积极参与临床中心。 该网站是所有ChiLDReN研究中最大的注册者之一，也是东南部唯一的ChiLDReN网站， 我们有基础设施继续，并可能扩大我们的能力，成功地招收和留住 参与者目的2：ASBT抑制剂在胆道闭锁（BA）中的开放标签安全性和耐受性试验。 没有治疗方法可以改善BA儿童的加塞门肠吻合术（KPE）的结局。一 BA中肝病的中枢病理生理恶化是胆汁酸的肝内滞留。我们将 在临床前和验证安全性数据的基础上进行2a期开放标签试点试验， ASBT抑制剂（ASBTi）在20个BA参与者中持续18个月，在KPE后不久开始。的这种减少 预计肝胆汁酸蓄积可改善对KPE的反应，并为2b期随访提供信息 ChiLDReN网络中的随机安慰剂对照研究。目标3：发现和验证 BASM的遗传原因最近一轮ChiLDReN支持的一个主要翻译组成部分是 一直致力于利用现代基因组技术。具体来说，我们已经开始测试 一种范式改变假说，即BA伴脾畸形综合征存在遗传病因 （BASM），即存在发育侧化缺陷的患者亚组。第一候选基因 已经确定，但需要额外的遗传和实验室验证。采取协调一致的办法 随着细胞培养和多达5个基于CRISPR的flox'd小鼠品系的开发， 发现，并提供了一个试剂基地的研究社区在广大。目标4：发现 儿童原发性硬化性胆管炎的基因组和环境因素 （PSC）。最近资助的一项成人PSC多中心研究（RC 2 DK 118619; Lazarovirus PI）涉及 将临床数据与基因组学、转录组学、代谢组学、微生物和环境数据相结合 （麻烦的）分析，以确定PSC进展的原因和促成因素。我们将协同 RC 2的现有分析（包括位于埃默里的HERCULES组学中心）与 在新开发的儿科PSC观察性研究中收集的生物标本和临床数据。

Project Abstract The overarching aims of this Center are to help advance the clinical, research, and educational goals of the ChiLDReN grant with a particular emphasis on engaging cutting-edge genome studies as a basis for discovery, innovation, and improvements in outcomes and care. As such, the aims of this application are not only to provide comprehensive research opportunities for all children who fit enrollment criteria for ChiLDReN throughout the Southeastern US, but to embark upon 1 pilot clinical trial and 2 genomically-centered Translational Aims: Aim 1: Continued robust Clinical Center participation in all aspects of ChiLDReN. This site is one of the largest enrollers in all ChiLDReN studies, the only ChiLDReN site in the SouthEast, and we have the infrastructure to continue, and likely expand our ability to successfully enroll and retain participants. Aim 2: Open label safety and tolerability trial of an ASBT inhibitor in biliary atresia (BA). There are no treatments that improve the outcome of Kasai Portoenterostomy (KPE) in children with BA. A central pathophysiological exacerbant of liver disease in BA is intrahepatic retention of bile acids. We will build upon pre-clinical and exisiting safety data to perform a Phase 2a open label pilot trial of use of an ASBT inhibitor (ASBTi) in 20 BA participants for 18 months, starting soon after KPE. This reduction in hepatic bile acid accumulation is expected to improve the response to KPE, and inform a followup Phase 2b randomized placebo-controlled study in the ChiLDReN network. Aim 3: Discovery and validation of genetic causes of BASM. A major translational component of the recent cycle of ChiLDReN support has been a focus upon utilization of modern genomic technologies. Specifically, we have begun to test the paradigm-changing hypothesis that there is a genetic etiology for BA with splenic malformation syndrome (BASM), that subgroup of patients that present with developmental laterality defects. A first candidate gene has been identified, but additional genetic and lab-based validations are needed. A coordinated approach with cell culture and development of up to 5 CRISPR-based flox’d mouse lines will accelerate first-step discoveries and provide a reagent base for the research community at large. Aim 4: Discovery of genomic and environmental (exposomic) contributors to pediatric Primary Sclerosing Cholangitis (PSC). A recently funded multi- center study of Adult PSC (RC2 DK118619; Lazaridis PI) involves integrating clinical data with genomic, transcriptomic, metabolomic, microbial, and environmental (exposome) analyses to identify causes and contributors to the progression of PSC. We will synergize the existing analytics of the RC2 (including the Emory-based HERCULES omics center) paired with the biospecimen and clinical data collected in the newly- developed pediatric PSC observational study.