BCM/TCH CHOLESTATIC LIVER DISEASE CONSORTIUM

摘要 有一种迫切而强烈的需求尚未得到满足，即开发先进的非侵入性生物标记物 儿科肝病的纤维化和疾病严重程度。这对胆汁淤积剂尤其重要。 像胆道闭锁这样的疾病，纤维化的发展速度是惊人的。当前 测量能够以不同程度的精确度区分晚期纤维化/肝硬变 从最小的纤维化到没有纤维化。不幸的是，他们不能区分中间阶段。 它们也不足以重复性，不足以用作研究评估的终点 关于肝病进展的产品。肝脏疾病的非侵入性检测领域 是复杂且未解决的成人肝病，在儿科尤为困难。vt.给出 肝活检的侵袭性大多数儿科生物标记物的研究都不可靠 与纤维化的组织学指标相关。儿科肝病的肝纤维化类型 与成人的疾病不同。儿科基础纤维扫描的初步分析 由儿童进行的淤胆性肝病(FORCE-NCT 02922751)研究支持 纤维化在胆道闭锁、α-1抗胰酶缺乏症和阿拉格尔综合征中是明显的概念。 儿科肝病非侵入性标志物发展的范式转变是 这是正当的。这一转变应包括无偏见、无目标的方法来确定 生物标记物和与肝脏疾病进展的可重复参数的创新相关性。 目前的提案试图利用蛋白质捕获慢速减速的发现特性 由SomaLogic开发的SOMAscan分析中的改进适体试剂 原力研究的背景。将对255名部队参与者的血浆样本进行分析 使用SOMAscan。将使用稳健的分析技术来评估 血浆蛋白与临床特征、实验室参数的个体和组合 和生物标记物指数。这一分析将导致识别出一组独特的蛋白质， 与进展性肝病的特征有关，如肝脏僵硬、血小板计数、白蛋白和 生长参数。这些发现极有可能加速基本面 我们对儿童胆汁淤积性肝病的非侵入性评估和了解的进展。

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.