BCM/TCH CHOLESTATIC LIVER DISEASE CONSORTIUM

BCM/TCH 胆汁淤积性肝病联盟

• 批准号: 10215815
• 负责人: BENJAMIN L SHNEIDER
• 金额: $ 25.5万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-10 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10215815
• 关键词: Adult; Alagille Syndrome; Albumins; Biliary Atresia; Biological Assay; Biological Markers; Characteristics; Child; Child Support; Childhood; Cholestasis; Cirrhosis; Clinical; Complex; Development; Disease; Disease Progression; Evaluation; Fibrosis; Growth; Histologic; Individual; Investigation; Laboratories; Liver; Liver diseases; Measures; Nature; Participant; Pattern; Pediatrics; Plasma; Plasma Proteins; Platelet Count measurement; Probability; Proteins; Proteomics; Reagent; Reproducibility; Sampling; Secure; Set protein; Severity of illness; Techniques; Testing; aptamer; biomarker identification; cholestatic liver disease; indexing; innovation; liver biopsy; novel

Abstract There is a pressing and strong unmet need to develop noninvasive biomarkers of advancing fibrosis and disease severity in pediatric liver disease. This is particularly important for cholestatic disorders like biliary atresia, where the pace of development of fibrosis is remarkable. Current measures are able with varying degrees of precision to distinguish advanced fibrosis/cirrhosis from minimal to no fibrosis. Unfortunately, they are not able to differentiate intermediate stages of fibrosis, nor are they reproducible enough for use as endpoints in the evaluation of investigation products on liver disease progression. The field of noninvasive testing of hepatic disease, which is complex and unresolved in the liver disease of adults, is especially difficult in pediatrics. Given the invasive nature of liver biopsy most studies of biomarkers in pediatrics cannot be securely associated with histologic measures of fibrosis. The patterns of fibrosis in pediatric liver disease are distinct from diseases in adults. Preliminary analysis of the baseline FibroScan in Pediatric Cholestatic Liver Disease (FORCE -NCT 02922751) study performed by ChiLDReN supports the concept that fibrosis is distinct in biliary atresia, α-1 antitrypsin deficiency and Alagille syndrome. A paradigm shift in the development of noninvasive markers of pediatric liver disease is warranted. The shift should include unbiased nontargeted approaches to the identification of biomarkers and innovative correlation with reproducible parameters of liver disease progression. The current proposal seeks to leverage the discovery features of the protein-capture slow off-rate modified aptamer reagents that are part of SOMAscan assay developed by SomaLogic in the context of the FORCE study. Plasma samples from 255 FORCE participants will be analyzed using the SOMAscan. Robust analytical techniques will be used to assess the correlation of individual and combinations of plasma proteins with clinical characteristics, laboratory parameters and biomarker indices. This analysis will lead to the identification of a unique set of proteins that associate with features of advancing liver disease, like liver stiffness, platelet count, albumin and growth parameters. These findings have a very high probability of accelerating fundamental advances in our noninvasive assessment and understanding of pediatric cholestatic liver disease.

摘要 有一个迫切和强烈的未满足的需要，开发非侵入性生物标志物的进展 纤维化和疾病严重程度的关系。这对于胆汁淤积性的尤为重要 胆道闭锁等疾病，其中纤维化的发展速度是显著的。电流 测量能够以不同程度的精确度区分晚期纤维化/肝硬化 从轻微到无纤维化。不幸的是，他们无法区分中间阶段 也不足以作为研究评价的终点 产品对肝病的进展。肝脏疾病的无创检测领域， 在成人肝病中是复杂和未解决的，在儿科中尤其困难。给定 肝活检的侵入性，大多数儿科生物标志物的研究不能安全地 与纤维化的组织学测量相关。小儿肝病的纤维化类型 与成人疾病不同。儿科基线FibroScan的初步分析 由ChiLDReN进行的胆汁淤积性肝病（FORCE-NCT 02922751）研究支持 认为胆道闭锁、α-1抗胰蛋白酶缺乏症和Alagille综合征的纤维化程度不同。 儿科肝病非侵入性标志物开发的范式转变是 有正当理由这种转变应包括无偏见的非针对性方法，以确定 生物标志物和与肝病进展的可重复参数的创新相关性。 目前的建议旨在利用蛋白质捕获慢解离速率的发现特征 改良的适体试剂是SomaLogic在2009年开发的SOMAscan测定的一部分， 在FORCE研究的背景下。将分析255名FORCE参与者的血浆样本 使用SOMAScan。将使用稳健的分析技术评估以下方面的相关性： 具有临床特征、实验室参数的血浆蛋白的个体和组合 和生物标志物指数。这种分析将导致鉴定一组独特的蛋白质， 与进展性肝病的特征相关，如肝硬度，血小板计数，白蛋白和 生长参数这些发现有很高的可能性， 我们对儿童胆汁淤积性肝病的无创评估和理解的进展。