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）是非酒精性脂肪肝病的侵略性形式，是最常见的 美国儿童的肝病。该疾病影响了所有肥胖儿童的近1/3，据估计 约有700万儿童。治疗基于生活方式的改变，例如低糖饮食和 运动增加，但没有批准儿童或成人的治疗疗法。目前，诊断纳什 需要肝活检，它繁琐，昂贵且具有固有的风险。缺乏1）无创的 诊断NASH的生物标志物和2）NASH对治疗的药效/反应生物标志物是 许多人认为是该领域的重要障碍。需要这些生物标志物来促进临床 护理，将资源集中在疾病最进步的孩子上。他们需要 推动治疗性开发，因为纳什儿童被优先参加临床试验和 需要用于NASH的响应生物标志物成为临床试验的替代端点生物标志物 加速药物开发。该提案代表了解决这些问题 知识的重要差距。该项目将由小儿NAFLD专家Miriam Vos博士领导 在早期生物标志物发展研究中经验丰富。 Kristal Maner-Smith博士在内的共同研究人员， 脂肪态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 开发一个生物标志物来预测纳什并反映纳什对治疗的反应2 以下目标。 AIM 1将定义和验证一组代谢物和脂质诊断儿童的诊断。 AIM 2将定义和验证与与之相关的代谢物，脂质和临床变量 治疗引起的NASH改善。目标1和2都将利用异常高质量 来自NASH临床研究网络的样品可在NIDDK中央存储库中存放。 储存库血清样品可从两项儿科临床研究中获得，包括NAFLD数据库研究 和补品随机临床试验，并在及时收集到肝活检以及详细的 临床表型。验证队列和对照样品将从emory肝活检中得出 埃默里（Emory）正在进行的生物措施研究和持续的健康对照小儿队列。初步数据证明了 纳什（NASH）（包括肝细胞） 气囊，炎症和脂肪变性支持可行性。这些研究的目的是持续 对小儿纳什生物标志物领域的强大影响，并通过 有效诊断NASH和成功的纳什治疗发展。

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