Biomarker Discovery for Nonalcoholic Fatty Liver Disease in Children

项目摘要 非酒精性脂肪性肝炎（NASH）是非酒精性脂肪性肝病的侵袭性形式，最常见的是肝硬化。 美国儿童肝脏疾病这种疾病影响了近1/3的肥胖儿童，估计 大约有700万儿童。治疗是基于生活方式的改变，如低糖饮食， 增加运动，但没有治疗方法被批准用于儿童或成人。目前，NASH的诊断 需要肝活检，这是麻烦的，昂贵的，并具有固有的风险。1）非侵入性 诊断NASH的生物标志物和2）NASH对治疗的药效学/反应生物标志物是 许多人认为这是该领域的一个重要障碍。需要这些生物标志物来推进临床 护理，将资源集中在患有最严重疾病的儿童身上。他们需要 推动治疗开发，因为NASH儿童优先参与临床试验， NASH的应答生物标志物需要成为临床试验的替代终点生物标志物， 加快药物开发。这项建议是一项特殊的多学科努力，以解决这些问题。 知识上的重大差距。该项目将由儿科NAFLD专家Miriam Vos博士领导， 在早期生物标志物开发研究方面经验丰富。包括克里斯塔尔·曼纳·史密斯博士在内的共同研究者， 脂质组学专家Ayman阿基勒博士，机器学习和生物标志物发现专家。团队寻求 开发一组生物标志物来预测NASH，并通过两种方法反映NASH对治疗的反应。 的目标。目的1将定义和验证一组代谢物和脂质诊断儿童NASH。 目标2将定义和验证一组代谢物，脂质和临床变量， 治疗诱导NASH的改善。目标1和2都将利用异常高质量的 样本可从NASH临床研究网络获得并保存在NIDDK中央储存库中。 储存库血清样本来自两项儿科临床研究，包括NAFLD数据库研究 和TONIC随机临床试验，并在接近肝活检的时间收集，以及详细的 临床表型分析验证队列和对照样本将从Emory肝活检中抽取 生物储存库研究和正在埃默里进行的健康对照儿科队列研究。初步数据显示， 特定代谢物与NASH病理特征（包括肝细胞）之间存在强相关性 气球样变、炎症和脂肪变性支持可行性。这些研究的目的是要有一个持续的， 对儿科NASH生物标志物领域产生强大影响，并通过以下方式直接改善儿童健康 NASH的有效诊断和NASH的成功治疗开发。

Project Abstract Nonalcoholic steatohepatitis (NASH) is the aggressive form of nonalcoholic fatty liver disease, the most common liver disease in children in the United States. The disease affects almost 1/3 of all obese children, estimated to be approximately 7 million children. Treatment is based on lifestyle changes such as a low sugar diet and increasing exercise, but no therapeutics are approved for children or adults. Currently, diagnosis of NASH requires a liver biopsy, which is cumbersome, expensive and has inherent risk. The lack of 1) non-invasive biomarkers to diagnose NASH and 2) pharmacodynamic/response biomarkers of NASH to therapy are considered by many to be an important barrier in the field. These biomarkers are needed to advance clinical care, focusing resources on the children with the most progressive form of the disease. And they are needed to drive therapeutic development because children with NASH are prioritized for participation in clinical trials and response biomarkers for NASH are needed to become surrogate endpoint biomarkers for clinical trials to accelerate drug development. This proposal represents an exceptional multidisciplinary effort to address these important gaps in knowledge. The project will be led by Dr. Miriam Vos, expert in pediatric NAFLD and experienced in early biomarker development research. Co-investigators including Dr. Kristal Maner-Smith, expert in lipidomics and Dr. Ayman Akil, expert in machine learning and biomarker discovery. The team seeks to develop a panel of biomarkers to predict NASH and to reflect response of NASH to therapy through the 2 following aims. Aim 1 will define and validate a panel of metabolites and lipids diagnostic of NASH in children. Aim 2 will define and validate a panel of metabolites, lipids and clinical variables that are associated with treatment induced improvement in NASH. Aims 1 and 2 will both capitalize on the exceptionally high-quality samples available from the NASH clinical research network and deposited within the NIDDK Central Repository. Repository serum samples are available from two pediatric clinical studies including the NAFLD Database study and the TONIC randomized clinical trial and were collected near in time to a liver biopsy as well as with detailed clinical phenotyping. Validation cohort and control samples will be drawn from the Emory Liver Biopsy Biorepository study and an ongoing Healthy Control pediatric cohort at Emory. Preliminary data demonstrates strong associations between specific metabolites and pathologic features of NASH including hepatocyte ballooning, inflammation and steatosis supporting feasibility. These studies are designed to have a sustained, powerful impact on the pediatric NASH biomarker field and to directly improve the health of children through efficient diagnosis of NASH and successful therapeutic development for NASH.