Biomarker Discovery for Nonalcoholic Fatty Liver Disease in Children

儿童非酒精性脂肪肝的生物标志物发现

• 批准号: 10469568
• 负责人: MIRIAM B. VOS
• 金额: $ 34.16万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-16 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10469568
• 关键词: Address; Adult; Affect; Automobile Driving; Biological Assay; Biological Markers; Child; Child Health; Childhood; Cirrhosis; Clinical; Clinical Data; Clinical Research; Clinical Trials; Country; Data; Data Analyses; Databases; Deposition; Development; Diabetes Mellitus; Diagnosis; Diagnostic; Diet; Digestive System Disorders; Disease; Eligibility Determination; Exercise; Fibrosis; Funding; Goals; Hepatocyte; Inflammation; Kidney Diseases; Knowledge; Letters; Life Style; Lipids; Liver diseases; Machine Learning; Measures; Methods; Mission; Modeling; National Institute of Diabetes and Digestive and Kidney Diseases; Outcome; Pathologic; Pediatric cohort; Pharmaceutical Preparations; Pharmacodynamics; Pilot Projects; Primary carcinoma of the liver cells; Publishing; Randomized Clinical Trials; Research; Research Personnel; Resources; Risk; Sampling; Sampling Studies; Sensitivity and Specificity; Serum; Severities; Surrogate Endpoint; Techniques; Technology; Testing; Therapeutic; Time; United States; Universities; Urologic Diseases; Validation; Work; base; biobank; biomarker discovery; biomarker panel; circulating biomarkers; clinical care; clinical phenotype; cohort; data access; data reduction; deep learning; design; diabetes risk; disorder subtype; drug development; early detection biomarkers; experience; imaging modality; improved; lipidomics; liver biopsy; member; metabolomics; multidisciplinary; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel marker; obesity in children; pediatric non-alcoholic fatty liver disease; personalized medicine; repository; research and development; response; response biomarker; specific biomarkers; sugar; therapeutic development; tool

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.

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，是最常见的疾病 美国儿童肝病。该疾病影响了几乎 1/3 的肥胖儿童，估计 大约有700万儿童。治疗基于生活方式的改变，例如低糖饮食和 增加锻炼，但没有批准用于儿童或成人的治疗方法。目前，NASH的诊断 需要进行肝活检，这既麻烦又昂贵，并且具有固有的风险。缺乏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 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，将资源集中用于患有病情最严重的儿童。他们需要 推动治疗发展，因为 NASH 儿童优先参与临床试验和 NASH 反应生物标志物需要成为临床试验的替代终点生物标志物 加速药物开发。该提案代表了解决这些问题的特殊多学科努力 知识上的重大差距。该项目将由儿科 NAFLD 专家 Miriam Vos 博士领导 具有早期生物标志物开发研究经验。共同研究人员包括 Kristal Maner-Smith 博士， 脂质组学专家和机器学习和生物标志物发现专家 Ayman Akil 博士。团队寻求 开发一组生物标志物来预测 NASH 并通过 2 来反映 NASH 对治疗的反应 以下目标。目标 1 将定义并验证一组代谢物和脂质诊断儿童 NASH。 目标 2 将定义并验证一组与相关的代谢物、脂质和临床变量 治疗引起 NASH 的改善。目标 1 和 2 都将利用卓越的高质量 样本可从 NASH 临床研究网络获取并存放在 NIDDK 中央存储库中。 储存血清样本可从两项儿科临床研究中获得，包括 NAFLD 数据库研究 和 TONIC 随机临床试验，并在接近肝活检时收集并详细记录 临床表型。验证队列和对照样本将从埃默里大学肝脏活检中抽取 生物样本库研究和埃默里大学正在进行的健康控制儿科队列研究。初步数据表明 特定代谢物与 NASH 病理特征（包括肝细胞）之间的密切关联 气球样变性、炎症和脂肪变性支持可行性。这些研究旨在具有持续的、 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的健康 NASH 的有效诊断和 NASH 治疗的成功开发。

项目成果

Variation in Alanine Aminotransferase in Children with Non-Alcoholic Fatty Liver Disease.

• DOI: 10.3390/children9030374
• 发表时间: 2022-03-08
• 期刊: Children (Basel, Switzerland)
• 作者: Castillo-Leon E;Morris HL;Schoen C;Bilhartz J;McKiernan P;Miloh T;Palle S;Kabbany MN;Munoz B;Mospan AR;Rudolph B;Xanthakos SA;Vos MB;Target-Nash Investigators
• 通讯作者: Target-Nash Investigators